(alpha-substituted aralkylamino and heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, pharmaceutical compositions thereof, and their use in treating proliferative diseases

ABSTRACT

Provided herein are (alpha-substituted aralkylamino or heteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles, e.g., a compound of Formula I, and their pharmaceutical compositions, preparation, and use as agents or drugs for treating proliferative diseases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation U.S. application Ser. No. 16/789,954,filed Feb. 13, 2020, which is a continuation of U.S. application Ser.No. 16/389,371, filed Apr. 19, 2019, now U.S. Pat. No. 10,603,324,issued Mar. 31, 2020, which is a continuation of U.S. application Ser.No. 16/040,461, filed Jul. 19, 2018, now U.S. Pat. No. 10,335,415,issued Jul. 2, 2019, which is a continuation of U.S. application Ser.No. 14/729,700, filed Jun. 3, 2015, now U.S. Pat. No. 10,064,868, issuedSep. 4, 2018, which is a continuation of U.S. application Ser. No.13/431,716, filed Mar. 27, 2012, now U.S. Pat. No. 9,056,852, issuedJun. 16, 2015, which claims the benefit of the priority of U.S.Provisional Application Nos. 61/468,502, filed Mar. 28, 2011;61/530,859, filed Sep. 2, 2011; and 61/560,699, filed Nov. 16, 2011; thedisclosure of each of which is incorporated herein by reference in itsentirety.

FIELD

Provided herein are (alpha-substituted aralkylamino orheteroarylalkylamino) pyrimidinyl and 1,3,5-triazinyl benzimidazoles,and their pharmaceutical compositions, preparation, and use as agents ordrugs for treating proliferative diseases.

BACKGROUND

Phosphoinositide-3-kinases (PI3Ks) are a group of lipid kinases, whichphosphorylate the 3-hydroxyl of phosphoinositides. They are classifiedinto at least three classes (classes I, II, and III) and play animportant role in cellular signaling (Stephens et al., Curr. Opin.Pharmacol. 2005, 5, 357). Class I enzymes are further classified intoclasses Ia and Ib based on their mechanism of activation. Class 1a PI3Ksare heterodimeric structures consisting of a catalytic subunit (p110α,p110β, or p110δ) in complex with a regulatory p85 subunit, whileclass-Ib PI3K (p110γ) is structurally similar but lacks the p85regulatory subunit, and instead is activated by βγ subunits ofheterotrimeric G-proteins (Walker et al., Mol. Cell. 2000, 6, 909).

PI3Ks play a variety of roles in normal tissue physiology (Foukas &Shepherd, Biochem. Soc. Trans. 2004, 32, 330; Shepherd, Acta Physiol.Scand. 2005, 183, 3), with p110α having a specific role in cancergrowth, p110β in thrombus formation mediated by integrin α₁₁β₃ (Jacksonet al., Nat. Med. 2005, 11, 507), and p110γ in inflammation, rheumatoidarthritis, and other chronic inflammation states (Barber et al., Nat.Med. 2005, 11, 933; Camps et al., Nat. Med. 2005, 11, 936; Rommel etal., Nat. Rev. 2007, 7, 191; and Ito, et al., J. Pharm. Exp. Therap.2007, 321, 1). Therefore, there is a need for PI3K inhibitors fortreating cancer and/or inflammatory diseases.

SUMMARY OF THE DISCLOSURE

Provided herein is a compound of Formula I:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

X, Y, and Z are each independently N or CR^(X), with the proviso that atleast two of X, Y, and Z are nitrogen atoms; where R^(X) is hydrogen orC₁₋₆ alkyl;

R¹ and R² are each independently (a)hydrogen, cyano, halo, or nitro; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c) together withthe N atom to which they are attached form heterocyclyl;

R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴are linked together to form a bond, C₁₋₆ alkylene, C₁₋₆ heteroalkylene,C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene;

R^(5a) is (a) hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or(c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5c) is —(CR^(5f)R^(5g)) (C₆₋₁₄ aryl) or—(CR^(5f)R^(5g))_(n)-heteroaryl;

R^(5d) and R^(5e) are each independently (a) hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5f) and R^(5g) are each independently (a)hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c); or —S(O)₂NR^(1b)R^(1c); or (d) when one occurrenceof R^(5f) and one occurrence of R^(5g) are attached to the same carbonatom, the R^(5f) and R^(5g) together with the carbon atom to which theyare attached form a C₃₋₁₀ cycloalkyl or heterocyclyl;

R⁶ is hydrogen, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆, alkyl, or—SO₂—C₁₋₆ alkyl;

m is 0 or 1; and

n is 0, 1, 2, 3, or 4:

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, andheterocyclyl in R¹, R², R³, R⁴, R⁶, R^(X), R^(1a), R^(1b), R^(1c),R^(1d), R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), and R^(5g) isoptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q, wherein each substituent Q isindependently selected from (a) oxo, cyano, halo, and nitro; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, and heterocyclyl, each of which is furtheroptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a); and (c) —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein eachR^(a), R^(b), R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₆, alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl, each of which is furtheroptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a); or (iii) R^(b) and R^(c) togetherwith the N atom to which they are attached form heterocyclyl, which isfurther optionally substituted with one or more, in one embodiment, one,two, three, or four, substituents Q^(a); wherein each Q^(a) isindependently selected from the group consisting of (a) oxo, cyano,halo, and nitro; (b) C₁₋₆ alkyl, C₂.F alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl; and(c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g),—OR^(e), —OC(O)R^(e), —OC(O)OR^(e), —OC(O)NR^(f)R^(g),—OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e), —OS(O)NR^(f)R^(g),—OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h),—NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h),—NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g),—SR^(e), —S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(f)R^(g), and—S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f), R^(g), and R^(h) isindependently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (iii) R^(f) and R^(g) together with the N atom to whichthey are attached form heterocyclyl.

In one embodiment, m is 0; and R^(5a) and R^(5b) are each independently(a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d), —NR^(a)S(O)₂R^(1d),—NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a),—S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c).

Also provided herein are pharmaceutical compositions comprising acompound disclosed herein, e.g., a compound of Formula I, or anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; and one or morepharmaceutically acceptable excipients.

Furthermore, provided herein is a method for treating, preventing, orameliorating one or more symptoms of a PI3K-mediated disorder, disease,or condition in a subject, comprising administering to the subject atherapeutically effective amount of a compound disclosed herein, e.g., acompound of Formula I, or an enantiomer, a mixture of enantiomers, amixture of two or more diastereomers, or an isotopic variant thereof; ora pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof.

Provided herein is a method for treating, preventing, or amelioratingone or more symptoms of a PI3Kδ-mediated disorder, disease, or conditionin a subject, comprising administering to the subject a therapeuticallyeffective amount of a compound disclosed herein, e.g., a compound ofFormula I, or an enantiomer, a mixture of enantiomers, a mixture of twoor more diastereomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

Provided herein is a method for treating, preventing, or amelioratingone or more symptoms of a proliferative disease in a subject, comprisingadministering to the subject a therapeutically effective amount of acompound disclosed herein, e.g., a compound of Formula I, or anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.

Provided herein is a method for modulating PI3K activity, comprisingcontacting a PI3K with an effective amount of a compound disclosedherein, e.g., a compound of Formula I, or an enantiomer, a mixture ofenantiomers, a mixture of two or more diastereomers, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof.

Provided herein is a method for modulating PI3K activity, comprisingcontacting PI3K with an effective amount of a compound disclosed herein,e.g., a compound of Formula I, or an enantiomer, a mixture ofenantiomers, a mixture of two or more diastereomers, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof.

Provided herein is a method for selectively modulating PI3K activity,comprising contacting PI3K with an effective amount of a compounddisclosed herein, e.g., a compound of Formula I, or an enantiomer, amixture of enantiomers, a mixture of two or more diastereomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

DETAILED DESCRIPTION

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures inorganic chemistry, medicinal chemistry, and pharmacology describedherein are those well known and commonly employed in the art. Unlessdefined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this disclosure belongs.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), cow, pig, sheep, goat horse, dog, cat, rabbit,rat, or mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human subject, in one embodiment, a human.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a disorder, disease, or condition, or one ormore of the symptoms associated with the disorder, disease, orcondition; or alleviating or eradicating the cause(s) of the disorder,disease, or condition itself.

The terms “prevent,” “preventing,” and “prevention” are meant to includea method of delaying and/or precluding the onset of a disorder, disease,or condition, and/or its attendant symptoms; barring a subject fromacquiring a disorder, disease, or condition; or reducing a subject'srisk of acquiring a disorder, disease, or condition.

The term “therapeutically effective amount” are meant to include theamount of a compound that, when administered, is sufficient to preventdevelopment of, or alleviate to some extent, one or more of the symptomsof the disorder, disease, or condition being treated. The term“therapeutically effective amount” also refers to the amount of acompound that is sufficient to elicit the biological or medical responseof a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell,tissue, system, animal, or human, which is being sought by a researcher,veterinarian, medical doctor, or clinician.

The term “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refers to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, solvent, or encapsulating material. Inone embodiment, each component is “pharmaceutically acceptable” in thesense of being compatible with other ingredients of a pharmaceuticalformulation, and suitable for use in contact with the tissue or organ ofhumans and animals without excessive toxicity, irritation, allergicresponse, immunogenicity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. See, Remington: TheScience and Practice of Pharmacy, 21st Edition, Lippincott Williams &Wilkins. Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,5th Edition, Rowe et al., Eds., The Pharmaceutical Press and theAmerican Pharmaceutical Association: 2005, and Handbook ofPharmaceutical Additives, 3rd Edition, Ash and Ash Eds., GowerPublishing Company: 2007; Pharmaceutical Preformulation and Formulation,2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, Fla., 2009.

The term “about” or “approximately” means an acceptable error for aparticular value as determined by one of ordinary skill in the art,which depends in part on how the value is measured or determined. Incertain embodiments, the term “about” or “approximately” means within 1,2, 3, or 4 standard deviations. In certain embodiments, the term “about”or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

The terms “active ingredient” and “active substance” refer to acompound, which is administered, alone or in combination with one ormore pharmaceutically acceptable excipients, to a subject for treating,preventing, or ameliorating one or more symptoms of a disorder, disease,or condition. As used herein, “active ingredient” and “active substance”may be an optically active isomer of a compound described herein.

The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent”refer to a compound, or a pharmaceutical composition thereof, which isadministered to a subject for treating, preventing, or ameliorating oneor more symptoms of a disorder, disease, or condition.

The term “naturally occurring” or“native” when used in connection withbiological materials such as nucleic acid molecules, polypeptides, hostcells, and the like, refers to materials which are found in nature andare not manipulated by man. Similarly, “non-naturally occurring” or“non-native” refers to a material that is not found in nature or thathas been structurally modified or synthesized by man.

The term “PI3K” refers to a phosphoinositide 3-kinase or variantthereof, which is capable of phosphorylating the inositol ring of PI inthe D-3 position. The term “PI3K variant” is intended to includeproteins substantially homologous to a native PI3K, i.e., proteinshaving one or more naturally or non-naturally occurring amino aciddeletions, insertions, or substitutions (e.g., PI3K derivatives,homologs, and fragments), as compared to the amino acid sequence of anative PI3K. The amino acid sequence of a PI3K variant is at least about80% identical, at least about 90% identical, or at least about 95%identical to a native PI3K. Examples of PI3K include, but are notlimited to, p110α, p110β, p110δ, p110γ, PI3K-C2α, PI3K-C2β, PI3K-C2γ,Vps34, mTOR, ATM, ATR, and DNA-PK. See, Fry, Biochem. Biophys. Acta1994, 1226, 237-268; Vanhaesebroeck and Waterfield, Exp. Cell. Res.1999, 253, 239-254; and Fry, Breast Cancer Res. 2001, 3, 304-312. PI3Ksare classified into at least four classes. Class I includes p110α,p110β, p110δ, and p110γ. Class II includes PI3K-C2α, PI3K-C2β, andPI3K-C2γ. Class III includes Vps34. Class IV includes mTOR, ATM, ATR,and DNA-PK. In certain embodiments, the PI3K is a Class I kinase. Incertain embodiments, the PI3K is p110α, p110β, p110δ, or p110γ. Incertain embodiments, the PI3K is a variant of a Class I kinase. Incertain embodiments, the PI3K is a p110α mutant. Examples of p110αmutants include, but are not limited to, R38H, G106V, K111N, K227E,N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, E453Q,H710P, I800L, T1025S, M1043I, M1043V, H1047L, H1047R, and H1047Y(Ikenoue et al., Cancer Res. 2005, 65, 4562-4567; Gymnopoulos et al.,Proc. Natl. Acad. Sci., 2007, 104, 5569-5574). In certain embodiments,the PI3K is a Class II kinase. In certain embodiments, the PI3K isPI3K-C2α, PI3K-C2β, or PI3K-C2γ. In certain embodiments, the PI3K is aClass III kinase. In certain embodiments, the PI3K is Vps34. In certainembodiments, the PI3K is a Class IV kinase. In certain embodiments, thePI3K is mTOR, ATM, ATR, or DNA-PK.

The terms “PI3K-mediated disorder, disease, or condition” and “adisorder, disease, or condition mediated by PI3K” refer to a disorder,disease, or condition characterized by abnormal or dysregulated, e.g.,less than or greater than normal, PI3K activity. Abnormal PI3Kfunctional activity might arise as the result of PI3K overexpression incells, expression of PI3K in cells which normally do not express PI3K,or dysregulation due to constitutive activation, caused, for example, bya mutation in PI3K. A PI3K-mediated disorder, disease, or condition maybe completely or partially mediated by abnormal PI3K activity. Inparticular, PI3K-mediated disorder, disease, or condition is one inwhich modulation of a PI3K activity results in some effect on theunderlying disorder, disease, or condition, e.g., a PI3K inhibitorresults in some improvement in at least some of patients being treated.

The terms “p110δ-mediated disorder, disease, or condition,” “a disorder,disease, or condition mediated by p110δ,” “PI3Kδ-mediated disorder,disease, or condition,” and “a disorder, disease, or condition mediatedby PI3Kδ” refer to a disorder, disease, or condition characterized byabnormal or dysregulated, e.g., less than or greater than normal, p110δactivity. Abnormal p110δ functional activity might arise as the resultof p110δ overexpression in cells, expression of p110δ in cells whichnormally do not express p110δ, or dysregulation due to constitutiveactivation, caused, for example, by a mutation in p110δ. Ap110δ-mediated disorder, disease, or condition may be completely orpartially mediated by abnormal p110δ activity. In particular,p110δ-mediated disorder, disease, or condition is one in whichmodulation of a p110δ activity results in some effect on the underlyingdisorder, disease, or condition, e.g., a p110δ inhibitor results in someimprovement in at least some of patients being treated.

The term “alkyl” refers to a linear or branched saturated monovalenthydrocarbon radical, wherein the alkylene may optionally be substitutedwith one or more substituents Q as described herein. The term “alkyl”also encompasses both linear and branched alkyl, unless otherwisespecified. In certain embodiments, the alkyl is a linear saturatedmonovalent hydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to 15(C₁₋₁₅), 1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₄) carbon atoms, or branchedsaturated monovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15(C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein,linear C₁₋₆ and branched C₃₋₆ alkyl groups are also referred as “loweralkyl.” Examples of alkyl groups include, but are not limited to,methyl, ethyl, propyl (including all isomeric forms), n-propyl,isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl,sec-butyl, I-butyl, pentyl (including all isomeric forms), and hexyl(including all isomeric forms). For example, C₁₋₆ alkyl refers to alinear saturated monovalent hydrocarbon radical of 1 to 6 carbon atomsor a branched saturated monovalent hydrocarbon radical of 3 to 6 carbonatoms.

The term “alkylene” refers to a linear or branched saturated divalenthydrocarbon radical, wherein the alkylene may optionally be substitutedwith one or more substituents Q as described herein. The term “alkylene”encompasses both linear and branched alkylene, unless otherwisespecified. In certain embodiments, the alkylene is a linear saturateddivalent hydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to 15 (C₁₋₁₅),1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₆) carbon atoms, or branched saturateddivalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein, linear C₁₋₆and branched C₃₋₆ alkylene groups are also referred as “lower alkylene.”Examples of alkylene groups include, but are not limited to, methylene,ethylene, propylene (including all isomeric forms), n-propylene,isopropylene, butylene (including all isomeric forms), n-butylene,isobutylene, t-butylene, pentylene (including all isomeric forms), andhexylene (including all isomeric forms). For example, C₁₋₆ alkylenerefers to a linear saturated divalent hydrocarbon radical of 1 to 6carbon atoms or a branched saturated divalent hydrocarbon radical of 3to 6 carbon atoms.

The term “heteroalkylene” refers to a linear or branched saturateddivalent hydrocarbon radical that contains one or more heteroatoms eachindependently selected from O, S, and N in the hydrocarbon chain. Forexample, C₁₋₆ heteroalkylene refers to a linear saturated divalenthydrocarbon radical of 1 to 6 carbon atoms or a branched saturateddivalent hydrocarbon radical of 3 to 6 carbon atoms. In certainembodiments, the heteroalkylene is a linear saturated divalenthydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to 15 (C₁₋₁₅), 1 to 10(C₁₋₁₀), or 1 to 6 (C₃₋₆) carbon atoms, or branched saturated divalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein, linear C₁₋₆ andbranched C₃₋₆ heteroalkylene groups are also referred as “lowerheteroalkylene.” Examples of heteroalkylene groups include, but are notlimited to, —CH₂O—, —CH₂OCH₂—, —CH₂CH₂O—, —CH₂NH—, —CH₂NHCH₂—,—CH₂CH₂NH—, —CH₂S—, —CH₂SCH₂—, and —CH₂CH₂S—. In certain embodiments,heteroalkylene may also be optionally substituted with one or moresubstituents Q as described herein.

The term “alkenyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more, in one embodiment, one, two, three,four, or five, in another embodiment, one, carbon-carbon double bond(s).The alkenyl may be optionally substituted with one or more substituentsQ as described herein. The term “alkenyl” also embraces radicals having“cis” and “trans” configurations, or alternatively, “Z” and “E”configurations, as appreciated by those of ordinary skill in the art. Asused herein, the term “alkenyl” encompasses both linear and branchedalkenyl, unless otherwise specified. For example, C₂₋₆ alkenyl refers toa linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbonatoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6carbon atoms. In certain embodiments, the alkenyl is a linear monovalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10(C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branched monovalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkenyl groupsinclude, but are not limited to, ethenyl, propen-1-yl, propen-2-yl,allyl, butenyl, and 4-methylbutenyl.

The term “alkenylene” refers to a linear or branched divalenthydrocarbon radical, which contains one or more, in one embodiment, one,two, three, four, or five, in another embodiment, one, carbon-carbondouble bond(s). The alkenylene may be optionally substituted with one ormore substituents Q as described herein. Similarly, the term“alkenylene” also embraces radicals having “cis” and “trans”configurations, or alternatively, “E” and “Z” configurations. As usedherein, the term “alkenylene” encompasses both linear and branchedalkenylene, unless otherwise specified. For example, C₂₋₆ alkenylenerefer to a linear unsaturated divalent hydrocarbon radical of 2 to 6carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3to 6 carbon atoms. In certain embodiments, the alkenylene is a lineardivalent hydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branched divalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkenylene groupsinclude, but are not limited to, ethenylene, allylene, propenylene,butenylene, and 4-methylbutenylene.

The term “heteroalkenylene” refers to a linear or branched divalenthydrocarbon radical, which contains one or more, in one embodiment, one,two, three, four, or five, in another embodiment, one, carbon-carbondouble bond(s), and which contains one or more heteroatoms eachindependently selected from O, S, and N in the hydrocarbon chain. Theheteroalkenylene may be optionally substituted with one or moresubstituents Q as described herein. The term “heteroalkenylene” embracesradicals having a “cis” or “trans” configuration or a mixture thereof,or alternatively, a “Z” or “E” configuration or a mixture thereof, asappreciated by those of ordinary skill in the art. For example, C₂₋₆heteroalkenylene refers to a linear unsaturated divalent hydrocarbonradical of 2 to 6 carbon atoms or a branched unsaturated divalenthydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, theheteroalkenylene is a linear divalent hydrocarbon radical of 2 to 20(C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbonatoms, or a branched divalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3to 15 (C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examplesof heteroalkenylene groups include, but are not limited to, —CH═CHO—,—CH═CHOCH₂—, —CH═CHCH₂O—, —CH═CHS—, —CH═CHSCH₂—, —CH═CHCH₂S—, or—CH═CHCH₂NH—.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more, in one embodiment, one, two, three,four, or five, in another embodiment, one, carbon-carbon triple bond(s).The alkynyl may be optionally substituted with one or more substituentsQ as described herein. The term “alkynyl” also encompasses both linearand branched alkynyl, unless otherwise specified. In certainembodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbonatoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀),3 to 15 (C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms.Examples of alkynyl groups include, but are not limited to, ethynyl(—C≡CH) and propargyl (—CH₂C≡CH). For example, C₂₋₆ alkynyl refers to alinear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atomsor a branched unsaturated monovalent hydrocarbon radical of 3 to 6carbon atoms.

The term “cycloalkyl” refers to a cyclic saturated bridged and/ornon-bridged monovalent hydrocarbon radical, which may be optionallysubstituted with one or more substituents Q as described herein. Incertain embodiments, the cycloalkyl has from 3 to 20 (C₃₋₂₀), from 3 to15 (C₃₋₁₅), from 3 to 10 (C₃₋₁₀), or from 3 to 7 (C₃₋₇) carbon atoms.Examples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, and adamantyl.

The term “cycloalkenyl” refers to a cyclic unsaturated, nonaromaticbridged and/or non-bridged monovalent hydrocarbon radical, which may beoptionally substituted with one or more substituents Q as describedherein. In certain embodiments, the cycloalkenyl has from 3 to 20(C₃₋₂₀), from 3 to 15 (C₃₋₁₅), from 3 to 10 (C₃₋₁₀), or from 3 to 7(C₃₋₇) carbon atoms. Examples of cycloalkyl groups include, but are notlimited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl.

The term “aryl” refers to a monocyclic aromatic group and/or multicyclicmonovalent aromatic group that contain at least one aromatic hydrocarbonring. In certain embodiments, the aryl has from 6 to 20 (C₆₋₂₀), from 6to 15 (C₆₋₁₅), or from 6 to 10 (C₆₋₁₀) ring atoms. Examples of arylgroups include, but are not limited to, phenyl, naphthyl, fluorenyl,azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Arylalso refers to bicyclic or tricyclic carbon rings, where one of therings is aromatic and the others of which may be saturated, partiallyunsaturated, or aromatic, for example, dihydronaphthyl, indenyl,indanyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments,aryl may be optionally substituted with one or more substituents Q asdescribed herein.

The term “aralkyl” or “arylalkyl” refers to a monovalent alkyl groupsubstituted with one or more aryl groups. In certain embodiments, thearalkyl has from 7 to 30 (C₇₋₃₀), from 7 to 20 (C₇₋₂₀), or from 7 to 16(C₇₋₁₆) carbon atoms. Examples of aralkyl groups include, but are notlimited to, benzyl, 2-phenylethyl, and 3-phenylpropyl. In certainembodiments, the aralkyl are optionally substituted with one or moresubstituents Q as described herein.

The term “heteroaryl” refers to a monovalent monocyclic aromatic groupor monovalent polycyclic aromatic group that contain at least onearomatic ring, wherein at least one aromatic ring contains one or moreheteroatoms independently selected from O, S, N, and P in the ring. Aheteroaryl group is bonded to the rest of a molecule through itsaromatic ring. Each ring of a heteroaryl group can contain one or two Oatoms, one or two S atoms, one to four N atoms, and/or one or two Patoms, provided that the total number of heteroatoms in each ring isfour or less and each ring contains at least one carbon atom. In certainembodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to10 ring atoms. Examples of monocyclic heteroaryl groups include, but arenot limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl,oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl,tetrazolyl, triazinyl, and triazolyl. Examples of bicyclic heteroarylgroups include, but are not limited to, benzofuranyl, benzimidazolyl,benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl,benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl,imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl,isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl,isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl,pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl,quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl.Examples of tricyclic heteroaryl groups include, but are not limited to,acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl,phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, theheteroaryl may also be optionally substituted with one or moresubstituents Q as described herein as described herein.

The term “heterocyclyl” or “heterocyclic” refers to a monovalentmonocyclic non-aromatic ring system or monovalent polycyclic ring systemthat contains at least one non-aromatic ring, wherein one or more of thenon-aromatic ring atoms are heteroatoms independently selected from O,S, N, and P; and the remaining ring atoms are carbon atoms. In certainembodiments, the heterocyclyl or heterocyclic group has from 3 to 20,from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6ring atoms. A heterocyclyl group is bonded to the rest of a moleculethrough its non-aromatic ring. In certain embodiments, the heterocyclylis a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, whichmay be spiro, fused, or bridged, and in which nitrogen or sulfur atomsmay be optionally oxidized, nitrogen atoms may be optionallyquaternized, and some rings may be partially or fully saturated, oraromatic. The heterocyclyl may be attached to the main structure at anyheteroatom or carbon atom which results in the creation of a stablecompound. Examples of such heterocyclic groups include, but are notlimited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl,benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, β-carbolinyl,chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl,dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl,dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl,1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl,isobenzotetrahydrofuranyl, iso benzotetrahydrothienyl, isochromanyl,isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl,oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl,pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl,tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl,and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl may alsobe optionally substituted with one or more substituents Q as describedherein.

The term “halogen”, “halide” or “halo” refers to fluorine, chlorine,bromine, and/or iodine.

The term “optionally substituted” is intended to mean that a group orsubstituent, such as an alkyl, alkylene, heteroalkylene, alkenyl,alkenylene, heteroalkenylene, alkynyl, cycloalkyl, cycloalkenyl, aryl,aralkyl, heteroaryl, heteroaryl-C₁₋₆ alkyl, and heterocyclyl group, maybe substituted with one or more substituents Q, each of which isindependently selected from, e.g., (a) oxo (═O), halo, cyano(—CN), andnitro (—NO₂); (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl,each of which is further optionally substituted with one or more, in oneembodiment, one, two, three, four, or five, substituents Q³; and (c)—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c),—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c),—OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—P(O)R^(a)R^(d), —P(O)(OR^(a))R^(d), —P(O)(OR^(a))(OR^(d)), —SR^(a),—S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c),wherein each R^(a), R^(b), R^(c), and R^(5d) is independently (i)hydrogen; (ii) C₁₋₆, alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl, eachof which is optionally substituted with one or more, in one embodiment,one, two, three, or four, substituents Q^(a); or (iii) R^(b) and R^(c)together with the N atom to which they are attached form heteroaryl orheterocyclyl, optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q^(a). As usedherein, all groups that can be substituted are “optionally substituted,”unless otherwise specified.

In one embodiment, each substituent Q^(a) is independently selected fromthe group consisting of (a) oxo, cyano, halo, and nitro; and (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₄aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e),—C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e),—OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R¹, —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g),—NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h),—NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g), —P(O)R^(e)R^(h),—P(O)(OR^(e))R^(h), —P(O)(OR^(e))(OR^(h)), —SR^(e), —S(O)R^(e),—S(O)₂R^(e), —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein eachR^(e), R^(f), R^(g), and R^(h) is independently (i)hydrogen, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (ii) R^(f) and R^(g) together with the Natom to which they are attached form heteroaryl or heterocyclyl.

In certain embodiments, “optically active” and “enantiomerically active”refer to a collection of molecules, which has an enantiomeric excess ofno less than about 50%, no less than about 70%, no less than about 80%,no less than about 90%, no less than about 91%, no less than about 92%,no less than about 93%, no less than about 94%, no less than about 95%,no less than about 96%, no less than about 97%, no less than about 98%,no less than about 99%, no less than about 99.5%, or no less than about99.8%. In certain embodiments, the compound comprises about 95% or moreof the desired enantiomer and about 5% or less of the less preferredenantiomer based on the total weight of the racemate in question.

In describing an optically active compound, the prefixes R and S areused to denote the absolute configuration of the molecule about itschiral center(s). The (+) and (−) are used to denote the opticalrotation of the compound, that is, the direction in which a plane ofpolarized light is rotated by the optically active compound. The (−)prefix indicates that the compound is levorotatory, that is, thecompound rotates the plane of polarized light to the left orcounterclockwise. The (+) prefix indicates that the compound isdextrorotatory, that is, the compound rotates the plane of polarizedlight to the right or clockwise. However, the sign of optical rotation,(+) and (−), is not related to the absolute configuration of themolecule, R and S.

The term “isotopic variant” refers to a compound that contains anunnatural proportion of an isotope atone or more of the atoms thatconstitute such a compound. In certain embodiments, an “isotopicvariant” of a compound contains unnatural proportions of one or moreisotopes, including, but not limited to, hydrogen (¹H), deuterium (²H),tritium (³H), carbon-11 (¹¹C), carbon-12 (¹²C), carbon-13 (¹³C),carbon-14 (¹⁴C), nitrogen-13 (¹³N), nitrogen-14 (¹⁴N), nitrogen-15(¹⁵N), oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), oxygen-16 (¹⁶O), oxygen-17(¹⁷O), oxygen-18 (¹⁸O), fluorine-17 (¹⁷F), fluorine-18 (¹⁸F),phosphorus-31 (³¹P), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-32(³²S), sulfur-33 (³³S), sulfur-34 (³⁴S), sulfur-35 (³⁵S), sulfur-36(³⁶S), chlorine-35 (³⁵Cl), chlorine-36 (³⁶Cl), chlorine-37 (³⁷Cl),bromine-79 (⁷⁹Br), bromine-81 (⁸¹Br), iodine-123 (¹²³I), iodine-125(¹²⁵I), iodine-127 (¹²⁷I), iodine-129 (¹²⁹I), and iodine-131 (¹³¹I). Incertain embodiments, an “isotopic variant” of a compound is in a stableform, that is, non-radioactive. In certain embodiments, an “isotopicvariant” of a compound contains unnatural proportions of one or moreisotopes, including, but not limited to, hydrogen (¹H), deuterium (²H),carbon-12 (¹²C), carbon-13 (¹³C), nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N),oxygen-16 (¹⁶O), oxygen-17 (¹⁷O), oxygen-18 (¹⁸O), fluorine-17 (¹⁷F),phosphorus-31 (³¹P), sulfur-32 (³²S), sulfur-33 (³³S), sulfur-34 (³⁴S),sulfur-36 (³⁶S), chlorine-35 (³⁵Cl), chlorine-37 (³⁷Cl), bromine-79(⁷⁹Br), bromine-81 (⁸¹Br), and iodine-127 (¹²⁷I). In certainembodiments, an “isotopic variant” of a compound is in an unstable form,that is, radioactive. In certain embodiments, an “isotopic variant” of acompound contains unnatural proportions of one or more isotopes,including, but not limited to, tritium (³H), carbon-11 (¹¹C), carbon-14(¹⁴C), nitrogen-13 (¹³N), oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), fluorine-18(¹⁸F), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-35 (³⁵S),chlorine-36 (³⁶Cl), iodine-123 (¹²³I), iodine-125 (¹²⁵I), iodine-129(¹²⁹I), and iodine-131 (¹³¹I). It will be understood that, in a compoundas provided herein, any hydrogen can be ²H, for example, or any carboncan be ¹³C, for example, or any nitrogen can be ¹⁵N, for example, or anyoxygen can be ¹⁸O, for example, where feasible according to the judgmentof one of skill. In certain embodiments, an “isotopic variant” of acompound contains unnatural proportions of deuterium (D).

The term “solvate” refers to a complex or aggregate formed by one ormore molecules of a solute, e.g., a compound provided herein, and one ormore molecules of a solvent, which present in a stoichiometric ornon-stoichiometric amount. Suitable solvents include, but are notlimited to, water, methanol, ethanol, n-propanol, isopropanol, andacetic acid. In certain embodiments, the solvent is pharmaceuticallyacceptable. In one embodiment, the complex or aggregate is in acrystalline form. In another embodiment, the complex or aggregate is ina noncrystalline form. Where the solvent is water, the solvate is ahydrate. Examples of hydrates include, but are not limited to, ahemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, andpentahydrate.

The phrase “an enantiomer, a mixture of enantiomers, a mixture of two ormore diastereomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof”has the same meaning as the phrase “an enantiomer, a mixture ofenantiomers, a mixture of two or more diastereomers, or an isotopicvariant of the compound referenced therein; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug of the compound referencedtherein; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug of an enantiomer, a mixture of enantiomers, a mixture of two ormore diastereomers, or an isotopic variant of the compound referencedtherein.”

Compounds

In one embodiment, provided herein is a compound of Formula I:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

X, Y, and Z are each independently N or CR^(X), with the proviso that atleast two of X, Y, and Z are nitrogen atoms; where R^(X) is hydrogen orC₁₋₆ alkyl;

R¹ and R² are each independently (a)hydrogen, cyano, halo, or nitro; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₇R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c) together withthe N atom to which they are attached form heterocyclyl;

R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴are linked together to form a bond, C₁₋₆ alkylene, C₁₋₆ heteroalkylene,C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene;

R^(5a) is (a) hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—C(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or(c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c),

R^(5c) is —(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl) or—(CR^(5f)R^(5g))_(n)-heteroaryl;

R^(5d) and R^(5e) are each independently (a) hydrogen or halo: (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5f) and R^(5g) are each independently (a) hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c); or —S(O)₂NR^(1b)R^(1c); or (d) when one occurrenceof R^(5f) and one occurrence of R^(5g) are attached to the same carbonatom, the R^(5f) and R^(5g) together with the carbon atom to which theyare attached form a C₃₋₁₀ cycloalkyl or heterocyclyl:

R⁶ is hydrogen, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆ alkyl, or—SO₂—C₁₋₆ alkyl;

m is 0 or 1; and

n is 0, 1, 2, 3, or 4;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, andheterocyclyl in R¹, R², R³, R⁴, R⁶, R^(X), R^(1a), R^(1b), R^(1c),R^(1d), R^(5a), R^(5b), R^(5c), R^(5d), R^(5c), R^(5f), and R^(5g) isoptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q, wherein each substituent Q isindependently selected from (a) oxo, cyano, halo, and nitro; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, and heterocyclyl, each of which is furtheroptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a); and (c) —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein eachR^(a), R^(b), R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl, each of which is furtheroptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a); or (iii) R^(b) and R^(c) togetherwith the N atom to which they are attached form heterocyclyl, which isfurther optionally substituted with one or more, in one embodiment, one,two, three, or four, substituents Q^(a); wherein each Q^(a) isindependently selected from the group consisting of (a) oxo, cyano,halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl; and(c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g), —C(NR^(c))NR^(f)R^(g),—OR^(c), —OC(O)R^(c), —OC(O)OR^(e), —OC(O)NR^(f)R^(g),—OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(c), —OS(O)₂R^(c), —OS(O)NR^(f)R^(g),—OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(c)C(O)R^(h), —NR^(e)C(O)OR^(h),—NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h),—NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g), —NR^(c)S(O)₂NR^(f)R^(g),—SR^(e), —S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(f)R^(g), and—S(O)₂NR^(f)R^(g); wherein each R^(c), R^(f), R^(g), and R^(h) isindependently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (iii) R^(f) and R^(g) together with the N atom to whichthey are attached form heterocyclyl.

In one embodiment, in Formula I,

X, Y, and Z are each independently N or CR^(X) with the proviso that atleast two of X, Y, and Z are nitrogen atoms; where R^(X) is hydrogen orC₁₋₆ alkyl;

R¹ and R² are each independently (a)hydrogen, cyano, halo, or nitro; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c) together withthe N atom to which they are attached form heterocyclyl;

R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴are linked together to form a bond, C₁₋₆ alkylene, C₁₋₆ heteroalkylene,C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene;

R^(5a) is (a) hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (c) —C(O)R³, —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or(c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5c) is —(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl) or—(CR^(5f)R^(5g))_(n)-heteroaryl;

R^(5d) and R^(5e) are each independently (a) hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5f) and R^(5g) are each independently (a)hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c); or —S(O)₂NR^(1b)R^(1c); or (d) when one occurrenceof R^(5f) and one occurrence of R^(5g) are attached to the same carbonatom, the R^(5f) and R^(5g) together with the carbon atom to which theyare attached form a C₃₋₁₀ cycloalkyl or heterocyclyl;

R⁶ is hydrogen, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆ alkyl, or—SO₂—C₁₋₆ alkyl;

m is 0 or 1; and

n is 0, 1, 2, 3, or 4;

with the proviso that the compound is neither4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-N-(2-phenyl-2-(pyrrolidin-1-yl)ethyl)-1,3,5-triazin-2-aminenor6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(4-((R)-3-(methoxymethyl)morpholino)phenyl)ethyl)-2-morpholinopyrimidin-4-amine;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, andheterocyclyl is optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q as defined herein.

In another embodiment, in Formula I,

X, Y, and Z are each independently N or CR^(X), with the proviso that atleast two of X, Y, and Z are nitrogen atoms; where R^(X) is hydrogen orC₁₋₆ alkyl;

R¹ and R² are each independently (a)hydrogen, cyano, halo, or nitro; (b)C₁₋₄ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₄alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c) together withthe N atom to which they are attached form heterocyclyl;

R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴are linked together to form a bond, C₁₋₆ alkylene, C₁₋₆ heteroalkylene,C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene;

R^(5a) is (a) hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(3b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or(c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5c) is —(CR^(5f)R^(5g)), —(C₆₋₁₄ aryl) or—(CR^(5f)R^(5g))_(n)-heteroaryl;

R^(5d) and R^(5e) are each independently (a) hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5f) and R^(5g) are each independently (a)hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₅ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c); or —S(O)₂NR^(1b)R^(1c); or (d) when one occurrenceof R^(5f) and one occurrence of R^(5g) are attached to the same carbonatom, the R^(5f) and R^(5g) together with the carbon atom to which theyare attached form a C₃₋₁₀ cycloalkyl or heterocyclyl;

R⁶ is hydrogen, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆ alkyl, or—SO₂—C₁₋₆ alkyl;

m is 0 or 1; and

n is 0, 1, 2, 3, or 4;

with the proviso that, when X, Y, and Z are N, and R^(5a) is hydrogen,R^(5b) is not pyrrolidinyl; and when X and Z are N, Y is CH, and R^(5a)is hydrogen, R^(5b) is not 4-((R)-3-(methoxymethyl)morpholino)phenyl;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, andheterocyclyl is optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q as defined herein.

In yet another embodiment, in Formula I,

X, Y, and Z are each independently N or CR^(X), with the proviso that atleast two of X, Y, and Z are nitrogen atoms; where R^(X) is hydrogen orC₁₋₆ alkyl;

R¹ and R² are each independently (a) hydrogen, cyano, halo, or nitro;(b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c) together withthe N atom to which they are attached form heterocyclyl;

R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴are linked together to form a bond, C₁₋₆ alkylene, C₁₋₆ heteroalkylene,C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene;

R^(5a) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or(c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or(c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5c) is —(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl) or—(CR^(5f)R^(5g))_(n)-heteroaryl;

R^(5d) and R^(5e) are each independently (a) hydrogen or halo; (b)C₁₋₆alkyl, C₂₋₅ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5f) and R^(5g) are each independently (a)hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c); or —S(O)₂NR^(1b)R^(1c); or (d) when one occurrenceof R^(5f) and one occurrence of R^(5g) are attached to the same carbonatom, the R^(5f) and R^(5g) together with the carbon atom to which theyare attached form a C₃₋₁₀ cycloalkyl or heterocyclyl;

R⁶ is hydrogen, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆ alkyl, or—SO₂—C₁₋₆ alkyl;

m is 0 or 1; and

n is 0, 1, 2, 3, or 4;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, andheterocyclyl is optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q as defined herein.

In still another embodiment, in Formula I,

X, Y, and Z are N;

R¹ and R² are each independently (a)hydrogen, cyano, halo, or nitro; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c) together withthe N atom to which they are attached form heterocyclyl;

R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴are linked together to form a bond, C₁₋₆ alkylene, C₁₋₆ heteroalkylene,C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene;

R^(5a) is (a) hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, or heteroaryl; or (c)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5c) is —(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl) or—(CR^(5f)R^(5g))_(n)-heteroaryl;

R^(5d) and R^(5e) are each independently (a) hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₅ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5f) and R^(5g) are each independently (a)hydrogen or halo: (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c); or —S(O)₂NR^(1b)R^(1c); or (d) when one occurrenceof R^(5f) and one occurrence of R^(5g) are attached to the same carbonatom, the R^(5f) and R^(5g) together with the carbon atom to which theyare attached form a C₃₋₁₀ cycloalkyl or heterocyclyl;

R⁶ is hydrogen, C₁₋₆ alkyl, —S—C₁₋₄, alkyl, —S(O)—C₁₋₆ alkyl, or—SO₂—C₁₋₆ alkyl;

m is 0 or 1; and

n is 0, 1, 2, 3, or 4;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, andheterocyclyl is optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q as defined herein.

In one embodiment, the compound of Formula I has the structure ofFormula Ia:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(5c), R^(5d), R^(5c), m, X, Y, and Z are each asdefined herein. In one embodiment, m is 0. In another embodiment, m is1.

In another embodiment, the compound of Formula I has the structure ofFormula Ib:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof: wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(5c), R^(5d), R^(5e) m, X, Y, and Z are each asdefined herein. In one embodiment, m is 0. In another embodiment, m is1.

In one embodiment, provided herein is a compound of Formula I, Ia, or Ibas described herein, or an enantiomer, a mixture of enantiomers, amixture of two or more diastereomers, or an isotopic variant thereof; ora pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof; wherein m is 0; R^(5a) and R^(5b) are each independently(a)halo: (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); and R¹, R², R³, R⁴, R^(5c),R⁶, X, Y, Z, R^(1a), R^(1b), R^(1c), and R^(1d) are defined hereinelsewhere.

In yet another embodiment, provided herein is a compound of Formula II:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

X, Y, and Z are each independently N or CR^(X), with the proviso that atleast two of X, Y, and Z are nitrogen atoms; where R^(X) is hydrogen orC₁₋₆ alkyl;

R¹ and R² are each independently (a) hydrogen, cyano, halo, or nitro;(b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₅alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c) together withthe N atom to which they are attached form heterocyclyl;

R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴are linked together to form a bond, C₁₋₆ alkylene, C₁₋₆ heteroalkylene,C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene;

R^(5a) is (a) hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or(c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5c) is —(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl) or—(CR^(5f)R^(5g))_(n)-heteroaryl;

R^(5f) and R^(5g) are each independently (a)hydrogen or halo; (b) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c); or —S(O)₂NR^(1b)R^(1c); or (d) when one occurrenceof R^(5f) and one occurrence of R^(5g) are attached to the same carbonatom, the R^(5f) and R^(5g) together with the carbon atom to which theyare attached form a C₃₋₁₀ cycloalkyl or heterocyclyl:

R⁶ is hydrogen, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆ alkyl, or—SO₂—C₁₋₆ alkyl; and

n is 0, 1, 2, 3, or 4;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, andheterocyclyl in R¹, R², R³, R⁴, R⁶, R^(X), R^(1a), R^(1b), R^(1c),R^(1d), R^(5a), R^(5b), R^(5c), R^(5f), and R^(5g) is optionallysubstituted with one or more, in one embodiment, one, two, three, orfour, substituents Q, wherein each substituent Q is independentlyselected from (a) oxo, cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, and heterocyclyl, each of which is further optionallysubstituted with one or more, in one embodiment, one, two, three, orfour, substituents Q^(a); and (c) —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein eachR^(a), R^(b), R^(c), and R^(5d) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl, each of which is furtheroptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a); or (iii) R^(b) and R together withthe N atom to which they are attached form heterocyclyl, which isfurther optionally substituted with one or more, in one embodiment, one,two, three, or four, substituents Q^(a);

wherein each Q^(a) is independently selected from the group consistingof (a) oxo, cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(c)C(O)R^(h),—NR^(c)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(c)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) together with theN atom to which they are attached form heterocyclyl.

In yet another embodiment, provided herein is a compound of Formula II:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

X, Y, and Z are each independently N or CR^(X), with the proviso that atleast two of X, Y, and Z are nitrogen atoms; where R^(X) is hydrogen orC₁₋₆ alkyl;

R¹ and R² are each independently (a)hydrogen, cyano, halo, or nitro; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b),R^(1c), and R^(1d) is independently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c) together withthe N atom to which they are attached form heterocyclyl;

R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴are linked together to form a bond, C₁₋₆ alkylene, C₁₋₆ heteroalkylene,C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene;

R^(5a) is (a) hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or(c) —C(O)R¹³, —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R^(5c) is C₆₋₁₄ aryl or heteroaryl; and

R⁶ is hydrogen, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₆ alkyl, or—SO₂—C₁₋₆ alkyl;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, andheterocyclyl in R¹, R², R³, R⁴, R⁶, R^(X), R^(1a), R^(1b), R^(1c),R^(1d), R^(5a), R^(5b), and R^(5c) is optionally substituted with one ormore, in one embodiment, one, two, three, or four, substituents Q,wherein each substituent Q is independently selected from (a) oxo,cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl, each of which is further optionally substituted with oneor more, in one embodiment, one, two, three, or four, substituentsQ^(a); and (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(c), and R^(5d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl, each of which is further optionallysubstituted with one or more, in one embodiment, one, two, three, orfour, substituents Q^(a); or (iii) R^(b) and R^(c) together with the Natom to which they are attached form heterocyclyl, which is furtheroptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a);

wherein each Q^(a) is independently selected from the group consistingof (a) oxo, cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, andheterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(h), —NR^(c)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen, (ii) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) together with theN atom to which they are attached form heterocyclyl.

In one embodiment, the compound of Formula II has the structure ofFormula IIa:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(5c), X, Y, and Z are each as defined herein.

In another embodiment, the compound of Formula II has the structure ofFormula IIb:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(5c), X, Y, and Z are each as defined herein.

In one embodiment, provided herein is a compound of Formula II, IIa, orlib as described herein, or an enantiomer, a mixture of enantiomers, amixture of two or more diastereomers, or an isotopic variant thereof; ora pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof; wherein R^(5a) and R^(5b) are each independently (a) halo; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); and R¹, R², R³, R⁴, R^(5c),R⁶, X, Y, Z, R^(1a), R^(1b), R^(1c), and R^(1d) are defined hereinelsewhere.

In yet another embodiment, provided herein is a compound of Formula III:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R²,R³, R⁴, R⁶, R^(5a), R^(5b), R^(5c), R^(5d), R^(5c), and m are each asdefined herein. In one embodiment, m is 0. In another embodiment, m is1.

In one embodiment, the compound of Formula III has the structure ofFormula

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(5c), R^(5d), R^(1c), and m are each as definedherein. In one embodiment, m is 0. In another embodiment, m is 1.

In another embodiment, the compound of Formula III has the structure ofFormula IIIb:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(5c), R^(5d), R^(5c), and m are each as definedherein. In one embodiment, m is 0. In another embodiment, m is 1.

In one embodiment, provided herein is a compound of Formula III, IIIa,or IIIb as described herein, or an enantiomer, a mixture of enantiomers,a mixture of two or more diastereomers, or an isotopic variant thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof; wherein m is 0; R^(5a) and R^(5b) are each independently (a)halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); and R¹, R², R³, R⁴, R^(5c),R⁶, R^(1a), R^(1b), R^(1c), and R^(1d) are defined herein elsewhere.

In yet another embodiment, provided herein is a compound of Formula IV:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R²,R³, R⁴, R⁶, R^(5a), R^(5b), and R^(5c) are each as defined herein.

In one embodiment, the compound of Formula IV has the structure ofFormula IVa:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), and R^(5c) are each as defined herein.

In another embodiment, the compound of Formula IV has the structure ofFormula IVb:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), and R^(5c) are each as defined herein.

In one embodiment, provided herein is a compound of Formula IV, IVa, orIVb as described herein, or an enantiomer, a mixture of enantiomers, amixture of two or more diastereomers, or an isotopic variant thereof; ora pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof; wherein R^(5a) and R^(5b) are each independently (a)halo; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); and R¹, R², R³, R⁴, R^(5c),R⁶, R^(1a), R^(1b), R^(1c), and R^(1d) are defined herein elsewhere.

In yet another embodiment, provided herein is a compound of Formula V:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof, or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R²,R³, R⁴, R⁶, R^(5b), R^(5c), X, Y, and Z are each as defined herein.

In one embodiment, the compound of Formula V has the structure ofFormula Va:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5b), R^(5c), X, Y, and Z are each as defined herein.

In another embodiment, the compound of Formula V has the structure ofFormula Vb:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5b), R^(5c), X, Y, and Z are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula VI:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R²,R³, R⁴, R⁶, R^(5b), and R^(5c) are each as defined herein.

In one embodiment, the compound of Formula VI has the structure ofFormula VIa:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5b), and R^(5c) are each as defined herein.

In another embodiment, the compound of Formula VI has the structure ofFormula VIb:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5b), and R^(5c) are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula VII:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R^(7a), R^(7b), R^(7c), R^(7d), and R^(7c) are each independently (a)hydrogen, cyano, halo, or nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one or moresubstituents Q; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

two of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) that are adjacent toeach other form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each optionally substituted with one or more substituentsQ; and

R¹, R², R³, R⁴, R⁶, R^(1a), R^(1b), R^(1c), R^(1d), R^(5a), R^(5b), X,Y, and Z are each as defined herein.

In one embodiment, the compound of Formula VII has the structure ofFormula VIIa:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z areeach as defined herein.

In another embodiment, the compound of Formula VII has the structure ofFormula VIIb:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(7a), R-h, R^(7c), R^(7d), R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment, provided herein is a compound of FormulaVIII:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R²,R³, R⁴, R⁶, R^(5a), R^(5b), R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e)are each as defined herein.

In one embodiment, the compound of Formula VIII has the structure ofFormula VIIIa:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) are each asdefined herein.

In another embodiment, the compound of Formula VIII has the structure ofFormula VIIIb:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(7a), R^(7b), R^(7c), R^(7d), and R^(7c) are each asdefined herein.

In yet another embodiment, provided herein is a compound of Formula IX:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) are each independently (a)hydrogen, cyano, halo, or nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one or moresubstituents Q; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

two of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) that are adjacent toeach other form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each optionally substituted with one or more substituentsQ; and

R¹, R², R³, R⁴, R⁶, R^(1a), R^(1b), R^(1c), R^(1d), R^(5a), R^(5b),R^(5d), R^(5e), X, Y, and Z are each as defined herein.

In one embodiment, the compound of Formula IX has the structure ofFormula IXa:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(5d), R^(5c), R^(7a), R^(7b), R^(7c), R^(7d), R^(7e),X, Y, and Z are each as defined herein.

In another embodiment, the compound of Formula IX has the structure ofFormula IXb;

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(5d), R^(5e), R^(7a), R^(7b), R^(7c), R^(7d), R^(7e),X, Y, and Z are each as defined herein.

In Formula IX, IXa, or IXb, in certain embodiments, one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one or moresubstituents Q; in certain embodiments, one of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) is C₆₋₁₄ aryl, e.g., phenyl, optionally substitutedwith one or more substituents Q; in certain embodiments, one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is heteroaryl, e.g., 5-membered or6-membered heteroaryl, optionally substituted with one or moresubstituents Q; in certain embodiments, one of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) is heterocyclyl, e.g., 5-membered or 6-memberedheterocyclyl, optionally substituted with one or more substituents Q; incertain embodiments, one of R^(7a), R^(7b), R^(c), R^(7d), and R^(7e) isphenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl,each optionally substituted with one or more substituents Q; in certainembodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) isphenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl,piperidinyl, or piperazinyl, each optionally substituted with one ormore substituents Q; in certain embodiments, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl,4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl, pyrozol-4-yl,1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl,1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and in certainembodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) isphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In Formula IX, IXa, or IXb, in certain embodiments, R^(7a) is C₆₋₁₄aryl, heteroaryl, or heterocyclyl, each of which is optionallysubstituted with one or more substituents Q; in certain embodiments,R^(7a) is C₆₋₁₄ aryl, e.g., phenyl, optionally substituted with one ormore substituents Q; in certain embodiments, R^(7a) is heteroaryl, e.g.,5-membered or 6-membered heteroaryl, optionally substituted with one ormore substituents Q; in certain embodiments, R^(7a) is heterocyclyl,e.g., 5-membered or 6-membered heterocyclyl, optionally substituted withone or more substituents Q; in certain embodiments, R^(7a) is phenyl,imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one or more substituents Q; in certainembodiments, R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl,pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionallysubstituted with one or more substituents Q; in certain embodiments,R^(7a) is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl,2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl,3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl,4-methoxyphenyl, imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and in certain embodiments, R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, I-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In one embodiment, in Formula IX, IXa, or IXb,

R¹ is hydrogen or —OR^(1a), where R^(1a) is C₁₋₆ alkyl, optionallysubstituted with one or more substituents Q;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₆₋₁₄ alkyl, optionally substituted with one or more substituentsQ;

R^(5a) and R^(5b) are each independently hydrogen, halo, C₁₋₆ alkyl,optionally substituted with one or more substituents Q;

R^(5d) and R^(5e) are each independently C₆₋₁₄ alkyl, optionallysubstituted with one or more substituents Q:

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7c) are hydrogen; and

X, Y, and Z are each independently N or CR^(x), with the proviso that atleast two of X, Y, and Z are N; where R^(X) is a hydrogen or C₁₋₆ alkyl,optionally substituted with one or more substituents Q.

In another embodiment, in Formula IX, IXa, or IXb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₆₋₁₄ alkyl, optionally substituted with one or more halo;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are each independently C₆₋₁₄ alkyl;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In yet another embodiment, in Formula IX, IXa, or IXb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are methyl;

R^(7a) is C₆₋₁₄ aryl, monocyclic heteroaryl, or monocyclic heterocyclyl,each of which is optionally substituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In yet another embodiment, in Formula IX, IXa, or IXb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are methyl;

R^(7a) is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-memberedheterocyclyl, each of which is optionally substituted with one or moresubstituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In yet another embodiment, in Formula IX, IXa, or IXb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R¹ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are methyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionallysubstituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In still another embodiment, in Formula IX, IXa, or IXb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are methyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one or moresubstituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In yet another embodiment, provided herein is a compound of Formula X:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R²,R³, R⁴, R⁶, R^(5a), R^(5b), R^(5d), R^(5e), R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) are each as defined herein.

In one embodiment, the compound of Formula X has the structure ofFormula Xa:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(5d), R^(5e), R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e) are each as defined herein.

In another embodiment, the compound of Formula X has the structure ofFormula Xb:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(5d), R^(5c), R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e) are each as defined herein.

In Formula X, Xa, or Xb, in certain embodiments, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is C₆₋₄ aryl, heteroaryl, or heterocyclyl,each of which is optionally substituted with one or more substituents Q;in certain embodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7c) is C₆₋₁₄ aryl, e.g., phenyl, optionally substituted with one ormore substituents Q; in certain embodiments, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is heteroaryl, e.g., 5-membered or 6-memberedheteroaryl, optionally substituted with one or more substituents Q; incertain embodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e)is heterocyclyl, e.g., 5-membered or 6-membered heterocyclyl, optionallysubstituted with one or more substituents Q; in certain embodiments, oneof R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl,pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionallysubstituted with one or more substituents Q; in certain embodiments, oneof R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl,pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, orpiperazinyl, each optionally substituted with one or more substituentsQ; in certain embodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e) is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl,2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl,3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl,4-methoxyphenyl, imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and in certain embodiments, one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In Formula X, Xa, or Xb, in certain embodiments, R^(7a) is C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each of which is optionally substitutedwith one or more substituents Q; in certain embodiments, R^(7a) is C₆₋₁₄aryl, e.g., phenyl, optionally substituted with one or more substituentsQ; in certain embodiments, R^(1a) is heteroaryl, e.g., 5-membered or6-membered heteroaryl, optionally substituted with one or moresubstituents Q; in certain embodiments, R^(7a) is heterocyclyl, e.g.,5-membered or 6-membered heterocyclyl, optionally substituted with oneor more substituents Q; in certain embodiments, R^(7a) is phenyl,imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one or more substituents Q; in certainembodiments, R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl,pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionallysubstituted with one or more substituents Q; in certain embodiments,R^(7a) is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl,2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl,3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl,4-methoxyphenyl, imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and in certain embodiments, R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In one embodiment, in Formula X, Xa, or Xb, R¹ is hydrogen or —OR^(1a),where R^(1a) is C₁₋₆ alkyl, optionally substituted with one or moresubstituents Q;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₆₋₁₄ alkyl, optionally substituted with one or more substituentsQ;

R^(5a) and R^(5b) are each independently hydrogen, halo, C₁₋₆ alkyl,optionally substituted with one or more substituents Q;

R^(5d) and R^(5e) are each independently C₆₋₁₄ alkyl, optionallysubstituted with one or more substituents Q;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In another embodiment, in Formula X, Xa, or Xb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₆₋₁₄ alkyl, optionally substituted with one or more halo;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are each independently C₆₋₁₄ alkyl;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In yet another embodiment, in Formula X, Xa, or Xb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are methyl;

R^(7a) is C₆₋₁₄ aryl, monocyclic heteroaryl, or monocyclic heterocyclyl,each of which is optionally substituted with one or more substituents Q;and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In yet another embodiment, in Formula X, Xa, or Xb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are methyl;

R^(7a) is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-memberedheterocyclyl, each of which is optionally substituted with one or moresubstituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In yet another embodiment, in Formula X, Xa, or Xb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are methyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionallysubstituted with one or more substituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In still another embodiment, in Formula X, Xa, or Xb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are hydrogen;

R^(5d) and R^(5e) are methyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one or moresubstituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7c) are hydrogen.

In yet another embodiment, provided herein is a compound of Formula XI:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R^(7a), R^(7b), R^(7c), R^(7d), and R^(7c) are each independently (a)hydrogen, cyano, halo, or nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one or moresubstituents Q; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

two of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7c) that are adjacent toeach other form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each optionally substituted with one or more substituentsQ; and

R¹, R², R³, R⁴, R⁶, R^(1a), R^(1b), R^(1c), R^(1d), R^(5a), R^(5b),R^(5f), R^(5g), X, Y, and Z are each as defined herein.

In one embodiment, the compound of Formula XI has the structure ofFormula XIa:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(5f)R^(5g), R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), X,Y, and Z are each as defined herein.

In another embodiment, the compound of Formula XI has the structure ofFormula XIb:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(5f), R^(5g), R^(7a), R^(7b), R^(7c), R^(7d), R^(7e),X, Y, and Z are each as defined herein.

In one embodiment, provided herein is a compound of Formula XI, XIa, orXIb as described herein, or an enantiomer, a mixture of enantiomers, amixture of two or more diastereomers, or an isotopic variant thereof; ora pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof; wherein R^(5a) and R^(5b) are each independently (a)halo; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); and R¹, R², R³, R⁴, R⁵,R^(5g), R⁶, R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, Z, R^(1a),R^(1b), R^(1c), and R^(1d) are defined herein elsewhere.

In Formula XI, XIa, or XIb, in certain embodiments, one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one or moresubstituents Q; in certain embodiments, one of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) is C₆₋₁₄ aryl, e.g., phenyl, optionally substitutedwith one or more substituents Q; in certain embodiments, one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is heteroaryl, e.g., 5-membered or6-membered heteroaryl, optionally substituted with one or moresubstituents Q; in certain embodiments, one of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) is heterocyclyl, e.g., 5-membered or 6-memberedheterocyclyl, optionally substituted with one or more substituents Q; incertain embodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e)is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each optionally substituted with one or more substituentsQ; in certain embodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substitutedwith one or more substituents Q; in certain embodiments, one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl,3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl,1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and in certainembodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) isphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In Formula XI, XIa, or XIb, in certain embodiments, R^(7a) is C₆.a aryl,heteroaryl, or heterocyclyl, each of which is optionally substitutedwith one or more substituents Q; in certain embodiments, R^(1a) is C₆₋₁₄aryl, e.g., phenyl, optionally substituted with one or more substituentsQ; in certain embodiments, R^(7a) is heteroaryl, e.g., 5-membered or6-membered heteroaryl, optionally substituted with one or moresubstituents Q; in certain embodiments, R^(7a) is heterocyclyl, e.g.,5-membered or 6-membered heterocyclyl, optionally substituted with oneor more substituents Q; in certain embodiments, R^(1a) is phenyl,imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one or more substituents Q; in certainembodiments, R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl,pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionallysubstituted with one or more substituents Q; in certain embodiments,R^(7a) is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl,2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl,3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl,4-methoxyphenyl, imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and in certain embodiments, R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In one embodiment, in Formula XI, XIa, or XIb,

R¹ is hydrogen or —OR^(1a), where R^(1a) is C₁₋₆ alkyl, optionallysubstituted with one or more substituents Q;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₆₋₁₄ alkyl, optionally substituted with one or more substituentsQ;

R^(5a) and R^(5b) are each independently C₆₋₁₄ alkyl, optionallysubstituted with one or more substituents Q;

R^(5f) and R^(5g) are each independently hydrogen, halo, C₁₋₆ alkyl,optionally substituted with one or more substituents Q; or R^(5f) andR^(5g) together with the carbon atom to which they are attached formC₁₋₁₀ cycloalkyl or heterocyclyl, each of which is optionallysubstituted with one or more substituents Q;

R^(7a) is C₆₋₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CR^(x), with the proviso that atleast two of X, Y, and Z are N; where R^(x) is a hydrogen or C₁₋₆ alkyl,optionally substituted with one or more substituents Q.

In another embodiment, in Formula XI, XIa, or XIb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₆₋₁₄ alkyl, optionally substituted with one or more halo;

R^(5a) and R^(5b) are each independently C₆₋₁₄ alkyl;

R^(5f) and R^(5g) are each independently hydrogen or C₁₋₆ alkyl; orR^(5f) and R^(5g) together with the carbon atom to which they areattached form C₁₋₁₀ cycloalkyl;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In yet another embodiment, in Formula XI, XIa, or XIb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(5f) and R^(5g) are hydrogen; or R^(5f) and R^(5g) together with thecarbon atom to which they are attached form cyclopropyl, cyclobutyl,cyclpentyl, or cyclohexyl;

R^(7a) is C₆₋₁₄ aryl, monocyclic heteroaryl, or monocyclic heterocyclyl,each of which is optionally substituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In yet another embodiment, in Formula XI, XIa, or XIb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R¹ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(5f) and R^(5g) are hydrogen; or R^(5f) and R^(5g) together with thecarbon atom to which they are attached form cyclopropyl, cyclobutyl,cyclpentyl, or cyclohexyl;

R^(7a) is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-memberedheterocyclyl, each of which is optionally substituted with one or moresubstituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In yet another embodiment, in Formula XI, XIa, or XIb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(5f) and R^(5g) are hydrogen; or R^(5f) and R^(5g) together with thecarbon atom to which they are attached form cyclopropyl, cyclobutyl,cyclpentyl, or cyclohexyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionallysubstituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In still another embodiment, in Formula XI, XIa, or XIb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(5f) and R^(5g) are hydrogen; or R^(5f) and R^(5g) together with thecarbon atom to which they are attached form cyclopropyl, cyclobutyl,cyclpentyl, or cyclohexyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one or moresubstituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In yet another embodiment, provided herein is a compound of Formula XII:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R²,R³, R⁴, R⁶, R^(5a), R^(5b), R^(5f), R^(5g), R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) are each as defined herein.

In one embodiment, the compound of Formula XII has the structure ofFormula XIIa:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(5f), R^(5g), R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e) are each as defined herein.

In another embodiment, the compound of Formula XII has the structure ofFormula XIIb:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(5f), R^(5g), R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e) are each as defined herein.

In one embodiment, provided herein is a compound of Formula XII, XIIa,or XIIb as described herein, or an enantiomer, a mixture of enantiomers,a mixture of two or more diastereomers, or an isotopic variant thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof; wherein R^(5a) and R^(5b) are each independently (a)halo; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR¹³C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); and R¹, R², R³, R⁴, R⁵,R^(5g), R⁶, R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), R^(1a), R^(1b),R^(1c), and R^(1d) are defined herein elsewhere.

In Formula XII, XIIa, or XIIb, in certain embodiments, one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one or moresubstituents Q; in certain embodiments, one of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) is C₆₋₁₄ aryl, e.g., phenyl, optionally substitutedwith one or more substituents Q; in certain embodiments, one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is heteroaryl, e.g., 5-membered or6-membered heteroaryl, optionally substituted with one or moresubstituents Q; in certain embodiments, one of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) is heterocyclyl, e.g., 5-membered or 6-memberedheterocyclyl, optionally substituted with one or more substituents Q; incertain embodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e)is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each optionally substituted with one or more substituentsQ; in certain embodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substitutedwith one or more substituents Q; in certain embodiments, one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl,3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl,1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and in certainembodiments, one of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) isphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In Formula XII, XIIa, or XIIb, in certain embodiments, R^(7a) is C₆₋₁₄aryl, heteroaryl, or heterocyclyl, each of which is optionallysubstituted with one or more substituents Q; in certain embodiments,R^(1a) is C₆₋₁₄ aryl, e.g., phenyl, optionally substituted with one ormore substituents Q; in certain embodiments, R^(7a) is heteroaryl, e.g.,5-membered or 6-membered heteroaryl, optionally substituted with one ormore substituents Q; in certain embodiments, R^(7a) is heterocyclyl,e.g., 5-membered or 6-membered heterocyclyl, optionally substituted withone or more substituents Q; in certain embodiments, R^(1a) is phenyl,imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one or more substituents Q; in certainembodiments, R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl,pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionallysubstituted with one or more substituents Q; in certain embodiments,R^(7a) is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl,2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl,3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl,4-methoxyphenyl, imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and in certain embodiments, one of R^(7a),R^(7b), R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In one embodiment, in Formula XII, XIIa, or XIIb,

R¹ is hydrogen or —OR^(1a), where R^(1a) is C₁₋₆ alkyl, optionallysubstituted with one or more substituents Q;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₆₋₁₄ alkyl, optionally substituted with one or more substituentsQ;

R^(5a) and R^(5b) are each independently C₆₋₁₄ alkyl, optionallysubstituted with one or more substituents Q;

R^(5f) and R^(5g) are each independently hydrogen, halo, C₁₋₆ alkyl,optionally substituted with one or more substituents Q; or R^(5f) andR^(5g) together with the carbon atom to which they are attached formC₁₋₁₀ cycloalkyl or heterocyclyl, each of which is optionallysubstituted with one or more substituents Q;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7c) are hydrogen.

In another embodiment, in Formula XII, XIIa, or XIIb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₆₋₁₄ alkyl, optionally substituted with one or more halo;

R^(5a) and R^(5b) are each independently C₆₋₁₄ alkyl;

R^(5f) and R^(5g) are each independently hydrogen or C₁₋₆ alkyl; orR^(5f) and R^(5g) together with the carbon atom to which they areattached form C₁₋₁₀ cycloalkyl;

R^(7a) is C₁₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In yet another embodiment, in Formula XII, XIIa, or XIIb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(5f) and R^(5g) are hydrogen; or R^(5f) and R^(5g) together with thecarbon atom to which they are attached form cyclopropyl, cyclobutyl,cyclpentyl, or cyclohexyl;

R^(7a) is C₆₋₁₄ aryl, monocyclic heteroaryl, or monocyclic heterocyclyl,each of which is optionally substituted with one or more substituents Q;and

R^(7b), R^(7c), R^(7d), and R^(1c) are hydrogen.

In yet another embodiment, in Formula XII, XIIa, or XIIb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(5f) and R^(5g) are hydrogen; or R^(5f) and R^(5g) together with thecarbon atom to which they are attached form cyclopropyl, cyclobutyl,cyclpentyl, or cyclohexyl;

R^(7a) is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-memberedheterocyclyl, each of which is optionally substituted with one or moresubstituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In yet another embodiment, in Formula XII, XIa, or XIIb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(5f) and R^(5g) are hydrogen; or R^(5f) and R^(5g) together with thecarbon atom to which they are attached form cyclopropyl, cyclobutyl,cyclpentyl, or cyclohexyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrmidinyl,pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionallysubstituted with one or more substituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In still another embodiment, in Formula XII, XIIa, or XIb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(5f) and R^(5g) are hydrogen; or R^(5f) and R^(5g) together with thecarbon atom to which they are attached form cyclopropyl, cyclobutyl,cyclpentyl, or cyclohexyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one or moresubstituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In yet another embodiment, provided herein is a compound of FormulaXIII:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R²,R³, R⁴, R⁶, R^(5b), R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Zare each as defined herein.

In one embodiment, the compound of Formula XIII has the structure ofFormula XIIIa:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5b), R^(7a), R⁷, R^(7c), R^(7d), R^(7e), X, Y, and Z are each asdefined herein.

In another embodiment, the compound of Formula XIII has the structure ofFormula XIIIb:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶, R^(b),R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z are each as definedherein.

In yet another embodiment, provided herein is a compound of Formula XIV:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R²,R³, R⁴, R⁶, R^(5b), R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) are eachas defined herein.

In one embodiment, the compound of Formula XIV has the structure ofFormula XIVa:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶, R^(b),R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) are each as defined herein.

In another embodiment, the compound of Formula XIV has the structure ofFormula XIVb:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶, R^(b),R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula XV:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R²,R³, R⁴, R⁶, R^(5a), R^(5b), R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), X,Y, and Z are each as defined herein.

In one embodiment, in Formula XV, one of R^(7a), R^(7b), R^(7c), R^(7d),and R^(7e) is C₆₋₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q; and R¹, R², R³,R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d),and R^(7e), X, Y, and Z are each as defined herein.

In another embodiment, in Formula XV, one of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) is C₆₋₁₄ aryl, which is optionally substituted withone or more substituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XV, one of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) is heteroaryl, which is optionally substituted withone or more substituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(1a), R^(7b), R^(7c), R^(7d), and R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XV, one of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) is 5-membered or 6-membered heteroaryl, which isoptionally substituted with one or more substituents Q; and R¹, R², R³,R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d),and R^(7c), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XV, one of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) is heterocyclyl, which is optionally substituted withone or more substituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XV, one of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) is 5-membered or 6-membered heterocyclyl, which isoptionally substituted with one or more substituents Q; and R¹, R², R³,R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d),and R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XV, one of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl, pyridinyl,piperidinyl, or piperazinyl, each optionally substituted with one ormore substituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XV, one of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl, pyridinyl,pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionallysubstituted with one or more substituents Q; and R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XV, one of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) is phenyl, 2-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl,3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl,4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3-morpholin-4-ylmethylphenyl, imidazol-1-yl, pyrozol-4-yl,1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In still another embodiment, in Formula XV, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl,4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl, pyrozol-4-yl,1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl,1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and R¹, R², R³, R⁴,R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In one embodiment, in Formula XV, R^(7a) is C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one or moresubstituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c),R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In another embodiment, in Formula XV, R^(7a) is C₆₋₁₄ aryl, which isoptionally substituted with one or more substituents Q; and R¹, R², R³,R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XV, R^(1a) is heteroaryl, which isoptionally substituted with one or more substituents Q; and R¹, R², R³,R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XV, R^(7a) is 5-membered or6-membered heteroaryl, which is optionally substituted with one or moresubstituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c),R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XV, R^(7a) is heterocyclyl, whichis optionally substituted with one or more substituents Q; and R¹, R²,R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Zare each as defined herein.

In yet another embodiment, in Formula XV, R^(7a) is 5-membered or6-membered heterocyclyl, which is optionally substituted with one ormore substituents Q; and

R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X,Y, and Z are each as defined herein.

In yet another embodiment, in Formula XV, R^(7a) is phenyl, imidazolyl,pyrozolyl, pyridinyl, pyrozolyl, piperidinyl, or piperazinyl, eachoptionally substituted with one or more substituents Q; and R¹, R², R³,R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XV, R^(7a) is phenyl, imidazolyl,pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, orpiperazinyl, each optionally substituted with one or more substituentsQ; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d),R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XV, R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl,1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In still another embodiment, in Formula XV, R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In one embodiment, in Formula XV,

R¹ is hydrogen or —OR^(1a), where R^(1a) is C₁₋₆ alkyl, optionallysubstituted with one or more substituents Q;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₆₋₁₄ alkyl, optionally substituted with one or more substituentsQ;

R^(5a) and R^(5b) are each independently C₆₋₁₄ alkyl, optionallysubstituted with one or more substituents Q;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CR^(x), with the proviso that atleast two of X, Y, and Z are N; where R^(x) is a hydrogen or C₁₋₆ alkyl,optionally substituted with one or more substituents Q.

In another embodiment, in Formula XV,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₆₋₁₄ alkyl, optionally substituted with one or more halo;

R^(5a) and R^(5b) are each independently C₆₋₁₄ alkyl;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In yet another embodiment, in Formula XV,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(7a) is C₆₋₁₄ aryl, monocyclic heteroaryl, or monocyclic heterocyclyl,each of which is optionally substituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In yet another embodiment, in Formula XV,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(7a) is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-memberedheterocyclyl, each of which is optionally substituted with one or moresubstituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In yet another embodiment, in Formula XV,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionallysubstituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In still another embodiment, in Formula XV,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one or moresubstituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In one embodiment, the compound of Formula XV has the structure ofFormula XVa.

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z areeach as defined herein.

In one embodiment, in Formula XVa, one of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each ofwhich is optionally substituted with one or more substituents Q; and R¹,R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In another embodiment, in Formula XVa, one of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) is C₆₋₁₄ aryl, which is optionally substituted withone or more substituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XVa, one of R^(7a), R^(7b),R^(7c), R^(17d), and R^(7e) is heteroaryl, which is optionallysubstituted with one or more substituents Q; and R¹, R², R³,

R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d),and R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVa, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is 5-membered or 6-membered heteroaryl, whichis optionally substituted with one or more substituents Q; and R¹, R²,R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVa, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is heterocyclyl, which is optionallysubstituted with one or more substituents Q; and R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7c), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVa, one of R^(7a), R^(7b),R^(7c), R^(17d), and R^(7e) is 5-membered or 6-membered heterocyclyl,which is optionally substituted with one or more substituents Q; and R¹,R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVa, one of R^(1a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl, pyridinyl,piperidinyl, or piperazinyl, each optionally substituted with one ormore substituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XVa, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl, pyridinyl,pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionallysubstituted with one or more substituents Q; and R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVa, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl,3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl,4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3-morpholin-4-ylmethylphenyl, imidazol-1-yl, pyrozol-4-yl,1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In still another embodiment, in Formula XVa, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl,4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl, pyrozol-4-yl,1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl,1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and R¹, R², R³, R⁴,R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In one embodiment, in Formula XVa, R^(7a) is C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one or moresubstituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(7a), R^(7b), R^(7c),R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In another embodiment, in Formula XVa, R^(7a) is C₆₋₁₄ aryl, which isoptionally substituted with one or more substituents Q; and R¹, R², R³,R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XVa, R^(7a) is heteroaryl, whichis optionally substituted with one or more substituents Q; and R¹, R²,R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Zare each as defined herein.

In yet another embodiment, in Formula XVa, R^(7a) is 5-membered or6-membered heteroaryl, which is optionally substituted with one or moresubstituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c),R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVa, R^(7a) is heterocyclyl, whichis optionally substituted with one or more substituents Q; and R¹, R²,R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Zare each as defined herein.

In yet another embodiment, in Formula XVa, R^(7a) is 5-membered or6-membered heterocyclyl, which is optionally substituted with one ormore substituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5e), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVa, R^(7a) is phenyl, imidazolyl,pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionallysubstituted with one or more substituents Q; and R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z are each asdefined herein.

In yet another embodiment, in Formula XVa, R^(7a) is phenyl, imidazolyl,pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, orpiperazinyl, each optionally substituted with one or more substituentsQ; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d),R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVa, R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In still another embodiment, in Formula XVa, R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In one embodiment, in Formula XVa,

R¹ is hydrogen or —OR¹³, where R^(1a) is C₁₋₆ alkyl, optionallysubstituted with one or more substituents Q;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₆₋₁₄ alkyl, optionally substituted with one or more substituentsQ;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl,optionally substituted with one or more substituents Q;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CR^(x), with the proviso that atleast two of X, Y, and Z are N; where R^(x) is a hydrogen or C₁₋₆ alkyl,optionally substituted with one or more substituents Q.

In another embodiment, in Formula XVa,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₆₋₁₄ alkyl, optionally substituted with one or more halo;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In yet another embodiment, in Formula XVa,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl;

R^(7a) is C₆₋₁₄ aryl, monocyclic heteroaryl, or monocyclic heterocyclyl,each of which is optionally substituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In yet another embodiment, in Formula XVa,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl;

R^(7a) is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-memberedheterocyclyl, each of which is optionally substituted with one or moresubstituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In yet another embodiment, in Formula XVa,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionallysubstituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In still another embodiment, in Formula XVa,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one or moresubstituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In another embodiment, the compound of Formula XV has the structure ofFormula XVb:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z areeach as defined herein.

In one embodiment, in Formula XVb, one of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) is C₆₋₄ aryl, heteroaryl, or heterocyclyl, each ofwhich is optionally substituted with one or more substituents Q; and R¹,R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In another embodiment, in Formula XVb, one of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) is C₆₋₁₄ aryl, which is optionally substituted withone or more substituents Q; and R¹, R², R³, R⁴,

R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVb, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is heteroaryl, which is optionallysubstituted with one or more substituents Q; and R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVb, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7c) is 5-membered or 6-membered heteroaryl, whichis optionally substituted with one or more substituents Q; and R¹, R²,R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVb, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is heterocyclyl, which is optionallysubstituted with one or more substituents Q; and R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVb, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7c) is 5-membered or 6-membered heterocyclyl,which is optionally substituted with one or more substituents Q; and R¹,R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVb, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7c) is phenyl, imidazolyl, pyrozolyl, pyridinyl,piperidinyl, or piperazinyl, each optionally substituted with one ormore substituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XVb, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl, pyridinyl,pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionallysubstituted with one or more substituents Q; and R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVb, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl,3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl,4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3-morpholin-4-ylmethylphenyl, imidazol-1-yl, pyrozol-4-yl,1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In still another embodiment, in Formula XVb, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl,4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl, pyrozol-4-yl,1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl,1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and R¹, R², R³, R⁴,R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In one embodiment, in Formula XVb, R^(7a) is C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one or moresubstituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c),R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In another embodiment, in Formula XVb, R^(7a) is C₆₋₁₄ aryl, which isoptionally substituted with one or more substituents Q; and R¹, R², R³,R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XVb, R^(7a) is heteroaryl, whichis optionally substituted with one or more substituents Q; and R¹, R²,R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Zare each as defined herein.

In yet another embodiment, in Formula XVb, R^(7a) is 5-membered or6-membered heteroaryl, which is optionally substituted with one or moresubstituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(7a), R^(7b), R^(7c),R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVb, R^(7a) is heterocyclyl, whichis optionally substituted with one or more substituents Q; and R¹, R²,R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Zare each as defined herein.

In yet another embodiment, in Formula XVb, R^(7a) is 5-membered or6-membered heterocyclyl, which is optionally substituted with one ormore substituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVb, R^(7a) is phenyl, imidazolyl,pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionallysubstituted with one or more substituents Q; and R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z are each asdefined herein.

In yet another embodiment, in Formula XVb, R^(7a) is phenyl, imidazolyl,pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, orpiperazinyl, each optionally substituted with one or more substituentsQ; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d),R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVb, R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl,I-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In still another embodiment, in Formula XVb, R^(1a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In one embodiment, in Formula XVb,

R¹ is hydrogen or —OR^(1a), where R^(1a) is C₁₋₆ alkyl, optionallysubstituted with one or more substituents Q;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₆₋₁₄ alkyl, optionally substituted with one or more substituentsQ;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl,optionally substituted with one or more substituents Q;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CR^(x), with the proviso that atleast two of X, Y, and Z are N; where R^(x) is a hydrogen or C₁₋₆ alkyl,optionally substituted with one or more substituents Q.

In another embodiment, in Formula XVb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₆₋₁₄ alkyl, optionally substituted with one or more halo;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In yet another embodiment, in Formula XVb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl;

R^(7a) is C₆₋₁₄ aryl, monocyclic heteroaryl, or monocyclic heterocyclyl,each of which is optionally substituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In yet another embodiment, in Formula XVb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl;

R^(7a) is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-memberedheterocyclyl, each of which is optionally substituted with one or moresubstituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In yet another embodiment, in Formula XVb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionallysubstituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In still another embodiment, in Formula XVb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one or moresubstituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In one embodiment, provided herein is a compound of Formula XV, XVa, orXVb as described herein, or an enantiomer, a mixture of enantiomers, amixture of two or more diastereomers, or an isotopic variant thereof; ora pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof; wherein R^(5a) and R^(5b) are each independently (a)halo; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); and R¹, R², R³, R⁴, R⁶,R^(7a), R^(7b), R^(7c), R-d, R^(7e), X, Y, Z, R^(1a), R^(1b), R^(1c),and R^(1d) are defined herein elsewhere.

In yet another embodiment, provided herein is a compound of Formula XVI:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R²,R³, R⁴, R⁶, R^(5a), R^(5b), R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e)are each as defined herein.

In one embodiment, in Formula XVI, one of R^(7a), R⁷¹, R^(7c), R^(7d),and R^(7c) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q; and R¹, R², R³,R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d),and R^(7c), X, Y, and Z are each as defined herein.

In another embodiment, in Formula XVI, one of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) is C₆₋₁₄ aryl, which is optionally substituted withone or more substituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7c), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XVI, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7c) is heteroaryl, which is optionallysubstituted with one or more substituents Q; and R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7c), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVI, one of R^(7a), R⁷⁶, R^(7c),R^(7d), and R^(7e) is 5-membered or 6-membered heteroaryl, which isoptionally substituted with one or more substituents Q; and R¹, R², R³,R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d),and R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVI, one of R^(7a), R⁷⁶, R^(7c),R^(7d), and R^(7e) is heterocyclyl, which is optionally substituted withone or more substituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XVI, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is 5-membered or 6-membered heterocyclyl,which is optionally substituted with one or more substituents Q; and R¹,R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVI, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl, pyridinyl,piperidinyl, or piperazinyl, each optionally substituted with one ormore substituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7c), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XVI, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl, pyridinyl,pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionallysubstituted with one or more substituents Q; and R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVI, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl,3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl,4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3-morpholin-4-ylmethylphenyl, imidazol-1-yl, pyrozol-4-yl,1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In still another embodiment, in Formula XVI, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl,4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl, pyrozol-4-yl,1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl,1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and R¹, R², R³, R⁴,R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In one embodiment, in Formula XVI, R^(7a) is C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one or moresubstituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c),R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In another embodiment, in Formula XVI, R^(7a) is C₆₋₁₄ aryl, which isoptionally substituted with one or more substituents Q; and R¹, R², R³,R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XVI, R^(7a) is heteroaryl, whichis optionally substituted with one or more substituents Q; and R¹, R²,R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Zare each as defined herein.

In yet another embodiment, in Formula XVI, R^(1a) is 5-membered or6-membered heteroaryl, which is optionally substituted with one or moresubstituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R, R^(7b), R^(7c),R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVI, R^(7a) is heterocyclyl, whichis optionally substituted with one or more substituents Q; and R¹, R²,R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Zare each as defined herein.

In yet another embodiment, in Formula XVI, R^(7a) is 5-membered or6-membered heterocyclyl, which is optionally substituted with one ormore substituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVI, R^(1a) is phenyl, imidazolyl,pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, each optionallysubstituted with one or more substituents Q; and R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z are each asdefined herein.

In yet another embodiment, in Formula XVI, R^(7a) is phenyl, imidazolyl,pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, orpiperazinyl, each optionally substituted with one or more substituentsQ; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7e), R^(7c), R^(7d),R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVI, R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In still another embodiment, in Formula XVI, R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In one embodiment, in Formula XVI,

R¹ is hydrogen or —OR^(1a), where R^(1a) is C₁₋₆ alkyl, optionallysubstituted with one or more substituents Q;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₆₋₁₄ alkyl, optionally substituted with one or more substituentsQ;

R^(5a) and R^(5b) are each independently C₆₋₁₄ alkyl, optionallysubstituted with one or more substituents Q;

R^(7a) is C₁₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In another embodiment, in Formula XVI,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₆₋₁₄ alkyl, optionally substituted with one or more halo;

R^(5a) and R^(5b) are each independently C₆₋₁₄ alkyl;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In yet another embodiment, in Formula XVI,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(7a) is C₆₋₁₄ aryl, monocyclic heteroaryl, or monocyclic heterocyclyl,each of which is optionally substituted with one or more substituents Q;and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In yet another embodiment, in Formula XVI,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(7a) is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-memberedheterocyclyl, each of which is optionally substituted with one or moresubstituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In yet another embodiment, in Formula XVI,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionallysubstituted with one or more substituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In still another embodiment, in Formula XVI,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are methyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one or moresubstituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment, the compound of Formula XVI has the structure ofFormula XVIa:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof: wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) are each asdefined herein.

In one embodiment, in Formula XVIa, one of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each ofwhich is optionally substituted with one or more substituents Q; and R¹,R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In another embodiment, in Formula XVIa, one of R^(7a), R^(7b), R^(7c),R^(7d), and R⁷ is C₆₋₁₄ aryl, which is optionally substituted with oneor more substituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XVIa, one of R^(1a), R^(7b),R^(7c), R^(7d), and R^(7e) is heteroaryl, which is optionallysubstituted with one or more substituents Q; and R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIa, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is 5-membered or 6-membered heteroaryl, whichis optionally substituted with one or more substituents Q; and R¹, R²,R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIa, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is heterocyclyl, which is optionallysubstituted with one or more substituents Q; and R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIa, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is 5-membered or 6-membered heterocyclyl,which is optionally substituted with one or more substituents Q; and R¹,R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIa, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl, pyridinyl,piperidinyl, or piperazinyl, each optionally substituted with one ormore substituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XVIa, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl, pyridinyl,pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionallysubstituted with one or more substituents Q; and R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIa, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl,3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl,4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3-morpholin-4-ylmethylphenyl, imidazol-1-yl, pyrozol-4-yl,1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In still another embodiment, in Formula XVIa, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl,4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl, pyrozol-4-yl,1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl,1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and R¹, R², R³, R⁴,R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In one embodiment, in Formula XVIa, R^(7a) is C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with on e or moresubstituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c),R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In another embodiment, in Formula XVIa, R^(7a) is C₆₋₁₄ aryl, which isoptionally substituted with one or more substituents Q; and R¹, R², R³,R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XVIa, R^(7a) is heteroaryl, whichis optionally substituted with one or more substituents Q; and R¹, R²,R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Zare each as defined herein.

In yet another embodiment, in Formula XVIa, R^(7a) is 5-membered or6-membered heteroaryl, which is optionally substituted with one or moresubstituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c),R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIa, R^(7a) is heterocyclyl,which is optionally substituted with one or more substituents Q; and R¹,R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y,and Z are each as defined herein.

In yet another embodiment, in Formula XVIa, R^(7a) is 5-membered or6-membered heterocyclyl, which is optionally substituted with one ormore substituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIa, R^(7a) is phenyl,imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one or more substituents Q; and R¹, R², R³,R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XVIa, R^(7a) is phenyl,imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl,piperidinyl, or piperazinyl, each optionally substituted with one ormore substituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIa, R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In still another embodiment, in Formula XVIa, R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In one embodiment, in Formula XVIa,

R¹ is hydrogen or —OR^(1a), where R^(1a) is C₁₋₆ alkyl, optionallysubstituted with one or more substituents Q;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₆₋₁₄ alkyl, optionally substituted with one or more substituentsQ;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl,optionally substituted with one or more substituents Q;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In another embodiment, in Formula XVIa,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₆₋₁₄ alkyl, optionally substituted with one or more halo;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl;

R^(7a) is C₆₋₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In yet another embodiment, in Formula XVIa,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl;

R^(7a) is C₆₋₁₄ aryl, monocyclic heteroaryl, or monocyclic heterocyclyl,each of which is optionally substituted with one or more substituents Q;and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In yet another embodiment, in Formula XVIa,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl;

R^(7a) is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-memberedheterocyclyl, each of which is optionally substituted with one or moresubstituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In yet another embodiment, in Formula XVIa,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₄ alkyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrrolidinyl,piperidinyl, piperidinyl, or piperazinyl, each of which is optionallysubstituted with one or more substituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In still another embodiment, in Formula XVIa,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one or moresubstituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In another embodiment, the compound of Formula XVI has the structure ofFormula XVIb:

or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) are each asdefined herein.

In one embodiment, in Formula XVIb, one of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each ofwhich is optionally substituted with one or more substituents Q; and R¹,R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In another embodiment, in Formula XVIb, one of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e) is C₆₋₁₄ aryl, which is optionally substituted withone or more substituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XVIb, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is heteroaryl, which is optionallysubstituted with one or more substituents Q; and R¹, R², R³, R⁴, R⁶,R^(5a), R^(5e), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIb, one of R^(7a), R^(7b), R⁷,R^(7d), and R^(7e) is 5-membered or 6-membered heteroaryl, which isoptionally substituted with one or more substituents Q; and R¹, R², R³,R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d),and R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIb, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is heterocyclyl, which is optionallysubstituted with one or more substituents Q; and R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIb, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is 5-membered or 6-membered heterocyclyl,which is optionally substituted with one or more substituents Q; and R¹,R², R³, R⁴, R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c),R^(7d), and R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIb, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl, pyridinyl,piperidinyl, or piperazinyl, each optionally substituted with one ormore substituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), theremaining of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XVIb, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, imidazolyl, pyrozolyl, pyridinyl,pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each optionallysubstituted with one or more substituents Q; and R¹, R², R³, R⁴, R⁶,R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIb, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl,3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl,4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3-morpholin-4-ylmethylphenyl, imidazol-1-yl, pyrozol-4-yl,1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrolidin-3-yl, piperidin-4-yl,1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In still another embodiment, in Formula XVIb, one of R^(7a), R^(7b),R^(7c), R^(7d), and R^(7e) is phenyl, 2-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl,4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl, pyrozol-4-yl,1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl,1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and R¹, R², R³, R⁴,R⁶, R^(5a), R^(5b), the remaining of R^(7a), R^(7b), R^(7c), R^(7d), andR^(7e), X, Y, and Z are each as defined herein.

In one embodiment, in Formula XVIb, R^(7a) is C₆₋₁₄ aryl, heteroaryl, orheterocyclyl, each of which is optionally substituted with one or moresubstituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c),R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In another embodiment, in Formula XVIb, R^(7a) is C₆₋₁₄ aryl, which isoptionally substituted with one or more substituents Q; and R¹, R², R³,R⁴, R⁶, R^(5a), R^(5b), R^(7e), R^(7c), R^(7d), R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XVIb, R^(7a) is heteroaryl, whichis optionally substituted with one or more substituents Q; and R¹, R²,R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Zare each as defined herein.

In yet another embodiment, in Formula XVIb, R^(7a) is 5-membered or6-membered heteroaryl, which is optionally substituted with one or moresubstituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c),R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIb, R^(1a) is heterocyclyl,which is optionally substituted with one or more substituents Q; and R¹,R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y,and Z are each as defined herein.

In yet another embodiment, in Formula XVIb, R^(7a) is 5-membered or6-membered heterocyclyl, which is optionally substituted with one ormore substituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIb, R^(7a) is phenyl,imidazolyl, pyrozolyl, pyridinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one or more substituents Q; and R¹, R², R³,R⁴, R⁶, R^(5a), R^(5b), R^(7b), R^(7c), R^(7d), R^(7e), X, Y, and Z areeach as defined herein.

In yet another embodiment, in Formula XVIb, R^(7a) is phenyl,imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl, pyrrolidinyl,piperidinyl, or piperazinyl, each optionally substituted with one ormore substituents Q; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In yet another embodiment, in Formula XVIb, R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl,3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl,4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-morpholin-4-ylmethylphenyl, imidazol-1-yl,pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In still another embodiment, in Formula XVIb, R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl,imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl,2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or4-methylpiperazin-1-yl; and R¹, R², R³, R⁴, R⁶, R^(5a), R^(5e), R^(7b),R^(7c), R^(7d), R^(7e), X, Y, and Z are each as defined herein.

In one embodiment, in Formula XVIb,

R¹ is hydrogen or —OR^(1a), where R^(1a) is C₁₋₆ alkyl, optionallysubstituted with one or more substituents Q;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₆₋₁₄ alkyl, optionally substituted with one or more substituentsQ;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl,optionally substituted with one or more substituents Q;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In another embodiment, in Formula XVIb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₆₋₁₄ alkyl, optionally substituted with one or more halo;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In yet another embodiment, in Formula XVIb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl;

R^(7a) is C₆₋₁₄ aryl, monocyclic heteroaryl, or monocyclic heterocyclyl,each of which is optionally substituted with one or more substituents Q;and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In yet another embodiment, in Formula XVIb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl;

R^(7a) is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-memberedheterocyclyl, each of which is optionally substituted with one or moresubstituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In yet another embodiment, in Formula XVIb,

R^(t) is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionallysubstituted with one or more substituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In still another embodiment, in Formula XVIb,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one or moresubstituents Q; and

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.

In one embodiment, provided herein is a compound of Formula XVI, XVIa,or XVIb as described herein, or an enantiomer, a mixture of enantiomers,a mixture of two or more diastereomers, or an isotopic variant thereof;or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof; wherein R^(5a) and R^(5b) are each independently (a)halo; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); and R¹, R², R³, R⁴, R⁶,R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), R^(1a), R^(1b), R^(1c), andR^(1d) are defined herein elsewhere.

In one embodiment, in any of the formulae provided herein,

R¹ is hydrogen or —OR^(1a), where R^(1a) is C₁₋₆ alkyl, optionallysubstituted with one or more substituents Q;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₆₋₁₄ alkyl, optionally substituted with one or more substituentsQ;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyloptionally substituted with one or more substituents Q;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CR^(x), with the proviso that atleast two of X, Y, and Z are N; where R^(X) is a hydrogen or C₁₋₆ alkyl,optionally substituted with one or more substituents Q.

In another embodiment, in any of the formulae provided herein,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is C₆₋₁₄ alkyl, optionally substituted with one or more halo;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl;

R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7c) are hydrogen; and

X, Y, and Z are each independently N or CH.

In yet another embodiment, in any of the formulae provided herein,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl;

R^(7a) is C₆₋₁₄ aryl, monocyclic heteroaryl, or monocyclic heterocyclyl,each of which is optionally substituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In yet another embodiment, in any of the formulae provided herein,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₄ alkyl;

R^(7a) is phenyl, 5- or 6-membered heteroaryl, or 5- or 6-memberedheterocyclyl, each of which is optionally substituted with one or moresubstituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In yet another embodiment, in any of the formulae provided herein,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, pyrimidinyl,pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionallysubstituted with one or more substituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

In still another embodiment, in any of the formulae provided herein,

R¹ is hydrogen or methoxy;

R² is hydrogen;

R³ and R⁴ are hydrogen;

R⁶ is difluoromethyl;

R^(5a) and R^(5b) are each independently hydrogen or C₆₋₁₄ alkyl;

R^(7a) is phenyl, imidazolyl, pyrozolyl, pyridinyl, piperidinyl, orpiperazinyl, each of which is optionally substituted with one or moresubstituents Q;

R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen; and

X, Y, and Z are each independently N or CH.

The groups or variables, R¹, R², R³, R⁴, R⁶, R^(5a), R^(5b), R^(5c),R^(5d), R^(5e), R^(5f), R^(5g), R^(7a), R^(7b), R^(7c), R^(7d), R^(7e),m, n, X, Y, and Z in Formulae provided herein, e.g., Formulae I to XVI,Ia to XVIa, and Ib to XVIb are further defined in the embodimentsdescribed herein. All combinations of the embodiments provided hereinfor such groups and/or variables are within the scope of thisdisclosure.

In certain embodiments, R¹ is hydrogen. In certain embodiments, R¹ iscyano. In certain embodiments, R¹ is halo. In certain embodiments, R¹ isfluoro, chloro, bromo, or iodo. In certain embodiments, R¹ is nitro. Incertain embodiments, R¹ is C₁₋₆ alkyl, optionally substituted with oneor more substituents Q as described herein. In certain embodiments, R¹is C₂₋₆ alkenyl, optionally substituted with one or more substituents Qas described herein. In certain embodiments, R¹ is C₂₋₆ alkynyl,optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R¹ is C₃₋₁₀ cycloalkyl, optionallysubstituted with one or more substituents Q as described herein. Incertain embodiments, R¹ is C₆₋₁₄ aryl, optionally substituted with oneor more substituents Q as described herein. In certain embodiments, R¹is C₇₋₁₅ aralkyl, optionally substituted with one or more substituents Qas described herein. In certain embodiments, R¹ is heteroaryl,optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R¹ is heterocyclyl, optionallysubstituted with one or more substituents Q as described herein.

In certain embodiments, R¹ is —C(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R¹ is —C(O)OR^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R¹ is —C(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R¹ is —C(NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), andR^(1c) are each as defined herein. In certain embodiments, R¹ is—OR^(1a), wherein R^(1a) is as defined herein. In certain embodiments,R¹ is —O—C₁₋₆ alkyl, wherein the alkyl is optionally substituted withone or more substituents Q as described herein. In certain embodiments,R¹ is methoxy, ethoxy, propoxy, isopropoxy, or 3-dimethylaminopropoxy.In certain embodiments, R¹ is —OC(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R¹ is —OC(O)OR^(1a), wherein R^(1a) isas defined herein. In certain embodiments, R¹ is —OC(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R¹ is —OC(═NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b),and R^(1c) are each as defined herein. In certain embodiments, R¹ is—OS(O)R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R¹ is —OS(O)₂R^(1a), wherein R^(1a) is as defined herein.In certain embodiments, R¹ is —OS(O)NR^(1b)R^(1c), wherein R^(1b) andR^(1c) are each as defined herein. In certain embodiments, R¹ is—OS(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R¹ is —NR^(1b)R^(c), wherein R^(1b) andR^(1c) are each as defined herein. In certain embodiments, R¹ is—NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R¹ is —NR^(1a)C(O)OR^(1d), whereinR^(1a) and R^(1d) are each as defined herein. In certain embodiments, R¹is —NR^(1a)C(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) areeach as defined herein. In certain embodiments, R¹ is—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), wherein R^(1a), R^(1b), R^(1c), andR^(1d) are each as defined herein. In certain embodiments, R¹ is—NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R¹ is —NR^(1a)S(O)₂R^(1d), whereinR^(1a) and R^(1d) are each as defined herein. In certain embodiments, R¹is —NR^(1a)S(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) areeach as defined herein. In certain embodiments, R¹ is—NR^(1a)S(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R¹ is —SR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R¹ is —S(O)R^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R¹ is—S(O)₂R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R¹ is —S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R¹ is—S(O)₂NR^(1b)R^(1c); wherein R^(1b) and R^(1c) are each as definedherein.

In certain embodiments, R² is hydrogen. In certain embodiments, R² iscyano. In certain embodiments, R² is halo. In certain embodiments, R² isfluoro, chloro, bromo, or iodo. In certain embodiments, R² is nitro. Incertain embodiments, R² is C₁₋₆ alkyl, optionally substituted with oneor more substituents Q as described herein. In certain embodiments, R²is C₂₋₆ alkenyl, optionally substituted with one or more substituents Qas described herein. In certain embodiments, R² is C₂₋₆ alkynyl,optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R² is C₃₋₁₀ cycloalkyl, optionallysubstituted with one or more substituents Q as described herein. Incertain embodiments, R² is C₃₋₇ cycloalkyl, optionally substituted withone or more substituents Q as described herein. In certain embodiments,R² is C₆₋₁₄ aryl, optionally substituted with one or more substituents Qas described herein. In certain embodiments, R² is C₇₋₁₅ aralkyl,optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R² is heteroaryl, optionally substitutedwith one or more substituents Q as described herein. In certainembodiments, R² is heterocyclyl, optionally substituted with one or moresubstituents Q as described herein.

In certain embodiments, R² is —C(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R² is —C(O)OR^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R² is —C(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R² is —C(NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), andR^(1c) are each as defined herein. In certain embodiments, R² is—OR^(1a), wherein R^(1a) is as defined herein. In certain embodiments,R¹ is —O—C₁₋₆ alkyl, wherein the alkyl is optionally substituted withone or more substituents Q as described herein. In certain embodiments,R¹ is methoxy, ethoxy, propoxy, isopropoxy, or 3-dimethylaminopropoxy.In certain embodiments, R² is —OC(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R² is —OC(O)OR^(1a), wherein R^(1a) isas defined herein. In certain embodiments, R² is —OC(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R² is —OC(═NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b),and R^(1c) are each as defined herein. In certain embodiments, R² is—OS(O)R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R² is —OS(O)₂R^(1a), wherein R^(1a) is as defined herein.In certain embodiments, R² is —OS(O)NR^(1b)R^(1c), wherein R^(1b) andR^(1c) are each as defined herein. In certain embodiments, R² is—OS(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R² is —NR^(1b)R^(1c), wherein R^(1b) andR^(1c) are each as defined herein. In certain embodiments, R² is amino(—NH₂). In certain embodiments, R² is —NR^(1a)C(O)R^(1d), wherein R^(1a)and R^(1d) are each as defined herein. In certain embodiments, R² is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R² is —NR^(1a)C(O)NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R² is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), wherein R^(1a),R^(1b), R^(1c), and R^(1d) are each as defined herein. In certainembodiments, R² is —NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R² is—NR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R² is —NR^(1a)S(O)NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R² is —NR^(1a)S(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b),and R^(1c) are each as defined herein. In certain embodiments, R² is—SR^(1a), wherein R^(1a) is as defined herein. In certain embodiments,R² is —S(O)R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R² is —S(O)₂R^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R² is —S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c)are each as defined herein. In certain embodiments, R² is—S(O)₂NR^(1b)R^(1c); wherein R^(1b) and R^(1c) are each as definedherein.

In certain embodiments, R³ is hydrogen. In certain embodiments, R³ isC₁₋₆ alkyl, optionally substituted with one or more substituents Q asdescribed herein. In certain embodiments, R³ is hydrogen, methyl, ethyl,or propyl (e.g., n-propyl, isopropyl, or 2-isopropyl).

In certain embodiments, R⁴ is hydrogen. In certain embodiments, R⁴ isC₁₋₆ alkyl, optionally substituted with one or more substituents Q asdescribed herein. In certain embodiments, R⁴ is hydrogen, methyl, ethyl,or propyl (e.g., n-propyl, isopropyl, or 2-isopropyl).

In certain embodiments, R³ and R⁴ are linked together to form a bond. Incertain embodiments, R³ and R⁴ are linked together to form C₁₋₆alkylene, optionally substituted with one or more substituents Q asdescribed herein. In certain embodiments, R³ and R⁴ are linked togetherto form methylene, ethylene, or propylene, each optionally substitutedwith one or more substituents Q as described herein. In certainembodiments, R³ and R⁴ are linked together to form C₁₋₆ heteroalkylene,optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R³ and R⁴ are linked together to formC₂₋₆ alkenylene, optionally substituted with one or more substituents Qas described herein. In certain embodiments, R³ and R⁴ are linkedtogether to form C₂₋₆ heteroalkenylene, optionally substituted with oneor more substituents Q as described herein.

In certain embodiments, R⁶ is hydrogen. In certain embodiments, R⁶ isC₁₋₆ alkyl, optionally substituted with one or more substituents Q asdescribed herein. In certain embodiments, R⁶ is C₁₋₆ alkyl, optionallysubstituted with one or more, in one embodiment, one, two, or three,halo. In certain embodiments, R⁶ is C₁₋₆ alkyl, optionally substitutedwith one or more, in one embodiment, one, two, or three, fluoro. Incertain embodiments, R⁶ is methyl, fluoromethyl, difluoromethyl, ortrifluoromethyl. In certain embodiments, R⁶ is difluoromethyl. Incertain embodiments, R⁶ is —S—C₁₋₆ alkyl, wherein the alkyl isoptionally substituted with one or more substituents Q as describedherein. In certain embodiments, R⁶ is —S(O)—C₁₋₆ alkyl, wherein thealkyl is optionally substituted with one or more substituents Q asdescribed herein. In certain embodiments, R⁶ is —SO₂—C₁₋₆ alkyl, whereinthe alkyl is optionally substituted with one or more substituents Q asdescribed herein.

In certain embodiments, R^(5a) is hydrogen. In certain embodiments,R^(5a) is not hydrogen. In certain embodiments, R^(5a) is halo. Incertain embodiments, R^(5a) is fluoro, chloro, bromo, or iodo. Incertain embodiments, R^(5a) is C₁₋₆ alkyl, optionally substituted withone or more substituents Q as described herein. In certain embodiments,R^(5a) is methyl, ethyl, propyl, or butyl, each optionally substitutedwith one or more substituents Q as described herein. In certainembodiments, R^(5a) is methyl, ethyl, n-propyl, isopropyl, i-butyl,isobutyl, or 1-butyl. In certain embodiments, R^(5a) is methyl. Incertain embodiments, R^(5a) is C₂₋₆ alkenyl, optionally substituted withone or more substituents Q as described herein. In certain embodiments,R^(5a) is C₂₋₆ alkynyl, optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, R^(5a) isC₃₋₁₀ cycloalkyl, optionally substituted with one or more substituents Qas described herein. In certain embodiments, R^(5a) is C₃₋₇ cycloalkyl,optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R^(5a) is C₆₋₁₄ aryl, optionallysubstituted with one or more substituents Q as described herein. Incertain embodiments, R^(5a) is C₇₋₁₅ aralkyl, optionally substitutedwith one or more substituents Q as described herein. In certainembodiments, R^(5a) is heteroaryl, optionally substituted with one ormore substituents Q as described herein. In certain embodiments, R^(5a)is heterocyclyl, optionally substituted with one or more substituents Qas described herein.

In certain embodiments, R^(5a) is —C(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5a) is —C(O)OR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5a) is—C(O)OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substituted withone or more substituents Q as described herein. In certain embodiments,R^(5a) is —C(O)OCH₃. In certain embodiments, R^(5a) is—C(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5a) is —C(NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5a) is —OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5a) is —OC(O)R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5a) is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R^(5a) is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5a) is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5a) is —OS(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5a) is —OS(O)₂R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5a) is—OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5a) is —OS(O)₂NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(5a) is —NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5a) is amino (—NH₂). In certainembodiments, R^(5a) is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R^(5a) is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5a) is —NR^(1a)C(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5a) is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), whereinR^(1a), R^(1b), R^(1c), and R^(1d) are each as defined herein. Incertain embodiments, R^(5a) is —NR^(1a)S(O)R^(1d), wherein R^(1a) andR^(1d) are each as defined herein. In certain embodiments, R^(5a) is—NR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5a) is —NR^(1a)S(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5a) is —NR^(1a)S(O)₂NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R^(5a) is —SR^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R^(5a) is —S(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5a) is —S(O)₂R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5a) is—S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5a) is —S(O)₂NR^(1b)R^(1c); whereinR^(1b) and R^(1c) are each as defined herein.

In certain embodiments, R⁵ is (a)hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, orheteroaryl, each of which is optionally substituted with one or moresubstituents Q; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c). In certain embodiments,R^(5a) is (a) hydrogen or halo; or (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, or heteroaryl,each of which is optionally substituted with one or more substituents Q.

In certain embodiments, R^(5b) is halo. In certain embodiments, R^(5b)is fluoro, chloro, bromo, or iodo. In certain embodiments, R^(5b) isC₁₋₆ alkyl, optionally substituted with one or more substituents Q asdescribed herein. In certain embodiments, R^(5b) is methyl, ethyl,propyl, or butyl, each optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, R^(5b) ismethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. Incertain embodiments, R^(5b) is methyl. In certain embodiments, R^(5b) isC₂₋₆ alkenyl, optionally substituted with one or more substituents Q asdescribed herein. In certain embodiments, R^(5b) is C₂₋₆ alkynyl,optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R^(5b) is C₃₋₁₀ cycloalkyl, optionallysubstituted with one or more substituents Q as described herein. Incertain embodiments, R^(5b) is C₃₋₇ cycloalkyl, optionally substitutedwith one or more substituents Q as described herein. In certainembodiments, R^(5b) is C_(b).a aryl, optionally substituted with one ormore substituents Q as described herein. In certain embodiments, R^(5b)is C₇₋₁₅ aralkyl, optionally substituted with one or more substituents Qas described herein. In certain embodiments, R^(5b) is heteroaryl,optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R^(5b) is heterocyclyl, optionallysubstituted with one or more substituents Q as described herein. Incertain embodiments, R^(5b) is not heterocyclyl.

In certain embodiments, R^(5b) is —C(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5b) is —C(O)OR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5b) is—C(O)OR¹¹, wherein R^(1a) is C₁₋₆ alkyl, optionally substituted with oneor more substituents Q as described herein. In certain embodiments,R^(5b) is —C(O)OCH₃. In certain embodiments, R^(5b) is—C(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5b) is —C(NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5b) is —OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5b) is —OC(O)R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(b) is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R^(5b) is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5b) is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5b) is —OS(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5b) is —OS(O)₂R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(b) is—OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5b) is —OS(O)₂NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(5b) is —NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(b) is amino (—NH₂). In certainembodiments, R^(5b) is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R^(5b) is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5b) is —NR^(1a)C(O)NR^(1b)R^(1c),wherein R¹³, R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R^(5b) is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), wherein R^(1a),R^(1b), R^(1c), and R^(1d) are each as defined herein. In certainembodiments, R^(5b) is —NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R^(5b) is—NR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5b) is —NR^(1a)S(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5b) is —NR^(1a)S(O)₂NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R^(b) is —SR^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R^(5b) is —S(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5b) is —S(O)₂R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5b) is—S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5b) is —S(O)₂NR^(1b)R^(1c); whereinR^(1b) and R^(1c) are each as defined herein.

In certain embodiments, R^(5a) and R^(5b) are each independently methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl, eachoptionally substituted with one or more substituents Q as describedherein. In certain embodiments, R^(5a) and R^(5b) are each independentlymethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl, eachoptionally substituted with one or more halo. In certain embodiments,R^(5a) and R^(5b) are each independently methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, or t-butyl. In certain embodiments, R^(5a)and R^(5b) are each methyl.

In certain embodiments, R^(1c) is C₆₋₁₄ aryl, optionally substitutedwith one or more substituents Q as described herein. In certainembodiments, R^(5b) is C₆₋₁₄ aryl substituted at the 2-position with onesubstituent Q as described herein. In certain embodiments, R^(5c) isphenyl or naphthyl, each optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, R^(5c) isphenyl, naphtha-1-yl, or naphtha-2-yl, each optionally substituted withone or more substituents Q as described herein. In certain embodiments,R^(5c) is phenyl, 4-chlorophenyl, 4-methoxyphenyl, or naphtha-2-yl. Incertain embodiments, R^(5c) is heteroaryl, optionally substituted withone or more substituents as described herein. In certain embodiments,R^(5c) is monocyclic heteroaryl, optionally substituted with one or moresubstituents as described herein. In certain embodiments, R^(5c) is 5-or 6-membered heteroaryl, optionally substituted with one or moresubstituents as described herein. In certain embodiments, R^(5c) isbicyclic heteroaryl, optionally substituted with one or moresubstituents as described herein.

In certain embodiments, R⁵ is —(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl), whereinthe C₆₋₁₄ aryl is optionally substituted with one or more substituents Qas described herein. In certain embodiments, R^(5c) is benzyl,2-phenethyl, 3-phenylpropyl, or 4-phenylbutyl, wherein each of thephenyl moiety is optionally substituted with one or more substituents Qas described herein. In certain embodiments, R^(5c) is benzyl,2-phenethyl, 3-phenylpropyl, or 4-phenylbutyl. In certain embodiments,R^(5c) is benzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, cyanobenzyl,methylbenzyl, or methoxylbenzyl. In certain embodiments, R^(5c) is(naphthalen-1-yl)methyl, (naphthalen-2-yl)methyl2-(naphthalen-1-yl)ethyl, 2-(naphthalen-2-yl)ethyl,3-(naphthalen-1-yl)propyl, 3-(naphthalen-2-yl)propyl,4-(naphthalen-1-yl)butyl, or 4-(naphthalen-2-yl)butyl, wherein each ofthe naphthyl moiety is optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, n is 0 or 1.In one embodiment, n is 1. In one embodiment, n is 1, 2, 3, or 4. Incertain embodiments, R^(5c) is —CH₂—(C₆₋₁₄ aryl), wherein the C₆₋₁₄ arylis optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R^(5c) is —C(CH₃)₂-(C₆₋₁₄ aryl), whereinthe C₆₋₁₄ aryl is optionally substituted with one or more substituents Qas described herein. In certain embodiments, R^(5c) is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl or naphthyl is each optionallysubstituted with one or more substituents Q as described herein, suchas, e.g., optionally substituted with one or more F, Cl, Br, I, —CN,—CH₃, —CF₃, —OCH₃, or—OCF₃. In certain embodiments, R^(5c) is—CH₂-phenyl, —CH₂-naphtha-1-yl, or —CH₂-naphtha-2-yl, wherein the phenylor naphthyl is each optionally substituted with one or more substituentsQ as described herein, such as, e.g., optionally substituted with one ormore F, Cl, Br, I, —CN, —CH₃, —CF₃, —OCH₃, or —OCF₃. In certainembodiments, R^(5c) is —CH₂-phenyl, —CH-naphtha-1-yl, or—CH-naphtha-2-yl, wherein the phenyl or naphthyl is each optionallysubstituted with one or more F, Cl, Br, I, —CN, —CH₃, —CF₃, —OCH₃,—OCF₃. In other embodiments, R⁵ is —CH₂-phenyl, —CH₂-naphtha-1-yl, or—CH₂-naphtha-2-yl, wherein the phenyl or naphthyl is each optionallysubstituted with one or more F, Cl, Br, I, —CN, —CH₃, —CF₃, —OCH₃,—OCF₃, —O—(C₁₋₄ alkylene)-N—(C₁₋₄ alkyl)₂ (e.g., —O—CH₂CH₂—N(CH₃)₂),—O-heterocyclyl (e.g., —O—(N-methylpiperidinyl) or —O-piperidinyl),—O-heteroaryl (e.g., —O-pyridyl), —NH-heterocyclyl (e.g.,—NH—(N-methylpiperidinyl), —NH—(N-methylpyrrolidinyl), —NH-piperidinyl,or —NH-pyrrolidinyl), —NH-heteroaryl (e.g., —NH-pyridyl),—NCH₃-heterocyclyl (e.g., —NCH₃-(N-methylpiperidinyl),—NCH₃-(N-methylpyrrolidinyl), —NCH₃-piperidinyl, or —NCH₃-pyrrolidinyl),—NCH-heteroaryl (e.g., —NCH₃-pyridyl), heterocyclyl (e.g., piperidinyl,piperazinyl, N-methylpiperidinyl, or N-methylpiperazinyl), or heteroaryl(e.g., pyridyl or imidazolyl). In certain embodiments, R⁵ is—CH₂-phenyl, —C(CH₃)₂-phenyl, —CH₂-(2-methylphenyl),—CH₂-(2-methoxylphenyl), —CH₂-(2-fluorophenyl), —CH₂-(2-chlorophenyl),—CH₂-(2-bromophenyl), —CH₂-(3-methylphenyl), —CH₂-(3-methoxylphenyl),—CH₂-3-fluorophenyl), —CH₂-(3-chlorophenyl), —CH₂-(3-bromophenyl),—CH₂-(4-methylphenyl), —CH₂-(4-methoxylphenyl), —CH₂-(4-fluorophenyl),—CH₂-(4-chlorophenyl), —CH₂-(4-bromophenyl), —CH₂-naphtha-1-yl, or—CH₂-naphtha-2-yl.

In certain embodiments, R^(5c) is —(CR^(5f)R^(5g))—(C₆₋₁₄ aryl), whereinthe C₆₋₁₄ aryl is optionally substituted with one or more substituents Qas described herein, and wherein R^(5f) and R^(5g) together with thecarbon atom to which they are attached form a 3- to 6-memberedcycloalkyl or heterocyclyl. In one embodiment, R^(5c)cis-cyclopropyl-phenyl. In one embodiment, R^(c) is -cyclobutyl-phenyl.In one embodiment, R^(5c) is -cyclopentyl-phenyl. In one embodiment,R^(5c) is -cyclohexyl-phenyl.

In certain embodiments, R^(5c) is —(CR^(5f)R^(5g))_(n)-heteroaryl,wherein the heteroaryl is optionally substituted with one or moresubstituents Q as described herein, wherein n is defined hereinelsewhere. In certain embodiments, R^(5c) is —CH₂-(monocyclicheteroaryl), wherein the heteroaryl is optionally substituted with oneor more substituents as described herein. In certain embodiments, R^(5c)is —CH₂-(5- or 6-membered heteroaryl), wherein the heteroaryl isoptionally substituted with one or more substituents as describedherein. In certain embodiments, R^(5c) is —CH₂-(bicyclic heteroaryl),wherein the heteroaryl is optionally substituted with one or moresubstituents as described herein.

In certain embodiments, R^(5d) is hydrogen. In certain embodiments,R^(5d) is halo. In certain embodiments, R^(5d) is fluoro, chloro, bromo,or iodo. In certain embodiments, R^(5d) is C₁₋₆ alkyl, optionallysubstituted with one or more substituents Q as described herein. Incertain embodiments, R^(5d) is methyl, optionally substituted with oneor more substituents Q as described herein. In certain embodiments,R^(5d) is methyl. In certain embodiments, R^(5d) is methyl, ethyl,propyl, or butyl, each optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, R^(5d) ismethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. Incertain embodiments, R^(5d) is C₂₋₆ alkenyl, optionally substituted withone or more substituents Q as described herein. In certain embodiments,R^(5d) is C₂₋₆ alkynyl, optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, R^(5d) isC₃₋₁₀ cycloalkyl, optionally substituted with one or more substituents Qas described herein. In certain embodiments, R^(5d) is C₆₋₁₄ aryl,optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R^(5d) is C₇₋₁₅ aralkyl, optionallysubstituted with one or more substituents Q as described herein. Incertain embodiments, R^(5d) is heteroaryl, optionally substituted withone or more substituents Q as described herein. In certain embodiments,R^(5d) is heterocyclyl, optionally substituted with one or moresubstituents Q as described herein.

In certain embodiments, R^(5d) is —C(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5d) is —C(O)OR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5d) is—C(O)OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substituted withone or more substituents Q as described herein. In certain embodiments,R^(5d) is —C(O)OCH₃. In certain embodiments, R^(5d) is—C(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5d) is —C(NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5d) is —OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5d) is —OC(O)R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5d) is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R^(5d) is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5d) is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(1d) is —OS(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5d) is —OS(O)₂R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5d) is—OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5d) is —OS(O)₂NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(5d) is —NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5d) is amino (—NH₂). In certainembodiments, R^(5d) is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R^(5d) is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5d) is —NR^(1a)C(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5d) is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), whereinR^(1a), R^(1b), R^(1c), and R^(1d) are each as defined herein. Incertain embodiments, R^(5d) is —NR^(1a)S(O)R^(1d), wherein R^(1a) andR^(1d) are each as defined herein. In certain embodiments, R^(5d) is—NR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5d) is —NR^(1a)S(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5d) is —NR^(1a)S(O)₂NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R^(5d) is —SR^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R^(5d) is —S(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5d) is —S(O)₂R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5d) is—S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5d) is —S(O)₂NR^(1b)R^(1c); whereinR^(1b) and R^(1c) are each as defined herein.

In certain embodiments, R^(5e) is hydrogen. In certain embodiments,R^(5e) is halo. In certain embodiments, R^(5e) is fluoro, chloro, bromo,or iodo. In certain embodiments, R^(e) is C₁₋₆ alkyl, optionallysubstituted with one or more substituents Q as described herein. Incertain embodiments, R^(5e) is methyl, optionally substituted with oneor more substituents Q as described herein. In certain embodiments,R^(5e) is methyl. In certain embodiments, R^(5e) is methyl, ethyl,propyl, or butyl, each optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, R^(5e) ismethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or i-butyl. Incertain embodiments, R^(5e) is C₂₋₅ alkenyl, optionally substituted withone or more substituents Q as described herein. In certain embodiments,R^(5e) is C₂, alkynyl, optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, R^(5e) isC₃₋₁₀ cycloalkyl, optionally substituted with one or more substituents Qas described herein. In certain embodiments, R^(5e) is C₆₋₁₄ aryl,optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R^(5e) is C₇₋₁₅ aralkyl, optionallysubstituted with one or more substituents Q as described herein. Incertain embodiments, R^(5e) is heteroaryl, optionally substituted withone or more substituents Q as described herein. In certain embodiments,R^(5e) is heterocyclyl, optionally substituted with one or moresubstituents Q as described herein.

In certain embodiments, R^(5e) is —C(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5e) is —C(O)OR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5e) is—C(O)OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substituted withone or more substituents Q as described herein. In certain embodiments,R^(5e) is —C(O)OCH₃. In certain embodiments, R^(5e) is—C(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5e) is —C(NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5e) is —OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5e) is —OC(O)R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5e) is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R^(5e) is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R⁵ is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5e) is —OS(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5e) is —OS(O)₂R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5e) is—OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5e) is —OS(O)₂NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(5e) is —NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5e) is amino (—NH₂). In certainembodiments, R^(5e) is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R^(5e) is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5e) is —NR^(1a)C(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5e) is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), whereinR^(1a), R^(1b), R^(1c), and R^(1d) are each as defined herein. Incertain embodiments, R^(5e) is —NR^(a)S(O)R^(1d), wherein R¹ and R^(1d)are each as defined herein. In certain embodiments, R^(5e) is—NR^(a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5e) is —NR^(1a)S(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5e) is —NR^(a)S(O)₂NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R^(5c) is —SR^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R^(5e) is —S(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5e) is —S(O)₂R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5e) is—S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(1c) is —S(O)₂NR^(1b)R^(1c); whereinR^(1b) and R^(1c) are each as defined herein.

In certain embodiments, R^(5f) is hydrogen. In certain embodiments,R^(5f) is halo. In certain embodiments, R^(5f) is fluoro, chloro, bromo,or iodo. In certain embodiments, R^(5f) is C₁₋₆ alkyl, optionallysubstituted with one or more substituents Q as described herein. Incertain embodiments, R^(5f) is methyl, optionally substituted with oneor more substituents Q as described herein. In certain embodiments,R^(5f) is methyl. In certain embodiments, R^(5f) is methyl, ethyl,propyl, or butyl, each optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, R^(5f) ismethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. Incertain embodiments, R^(5f) is C₂₋₆ alkenyl, optionally substituted withone or more substituents Q as described herein. In certain embodiments,R^(5f) is C₂₋₆ alkynyl, optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, R^(5f) isC₃₋₁₀ cycloalkyl, optionally substituted with one or more substituents Qas described herein. In certain embodiments, R^(5f) is C₆₋₁₄ aryl,optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R^(5f) is C₇₋₁₅ aralkyl, optionallysubstituted with one or more substituents Q as described herein. Incertain embodiments, R^(5f) is heteroaryl, optionally substituted withone or more substituents Q as described herein. In certain embodiments,R^(5f) is heterocyclyl, optionally substituted with one or moresubstituents Q as described herein.

In certain embodiments, R^(5f) is —C(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5f) is —C(O)OR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5f) is—C(O)OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substituted withone or more substituents Q as described herein. In certain embodiments,R^(5f) is —C(O)OCH₃. In certain embodiments, R^(5f) is—C(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5f) is —C(NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5f) is —OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5f) is —OC(O)R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5f) is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R^(5f) is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5f) is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5f) is —OS(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5f) is —OS(O)₂R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5f) is—OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5f) is —OS(O)₂NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(5f) is —NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5f) is amino (—NH₂). In certainembodiments, R^(5f) is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R^(5f) is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5f) is —NR^(1a)C(O)NR^(1b)R^(1c),wherein R^(a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R^(5f) is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), wherein R^(1a),R^(1b), R^(1c), and R^(1d) are each as defined herein. In certainembodiments, R^(5f) is —NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R^(5f) is—NR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5f) is —NR^(1a)S(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5f) is —NR^(1a)S(O)₂NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R^(5f) is —SR^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R^(5f) is —S(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5f) is —S(O)₂R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5f) is—S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5f) is —S(O)₂NR^(1b)R^(1c); whereinR^(1b) and R^(1c) are each as defined herein.

In certain embodiments, R^(5g) is hydrogen. In certain embodiments,R^(5g) is halo. In certain embodiments, R^(5g) is fluoro, chloro, bromo,or iodo. In certain embodiments, R^(5g) is C₁₋₆ alkyl, optionallysubstituted with one or more substituents Q as described herein. Incertain embodiments, R^(5g) is methyl, optionally substituted with oneor more substituents Q as described herein. In certain embodiments,R^(5g) is methyl. In certain embodiments, R^(5g) is methyl, ethyl,propyl, or butyl, each optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, R^(5g) ismethyl, ethyl, i-propyl, isopropyl, n-butyl, isobutyl, or t-butyl. Incertain embodiments, R^(5g) is C₂₋₆ alkenyl, optionally substituted withone or more substituents Q as described herein. In certain embodiments,R^(5g) is C₂₋₆ alkynyl, optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, R^(5g) isC₃₋₁₀ cycloalkyl, optionally substituted with one or more substituents Qas described herein. In certain embodiments, R^(5g) is C₆₋₁₄ aryl,optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R³ is C₇₋₁₅ aralkyl, optionallysubstituted with one or more substituents Q as described herein. Incertain embodiments, R^(5g) is heteroaryl, optionally substituted withone or more substituents Q as described herein. In certain embodiments,R³ is heterocyclyl, optionally substituted with one or more substituentsQ as described herein.

In certain embodiments, R^(5g) is —C(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5g) is —C(O)OR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5g) is—C(O)OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substituted withone or more substituents Q as described herein. In certain embodiments,R^(5g) is —C(O)OCH₂. In certain embodiments, R^(5g) is—C(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5g) is —C(NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5g) is —OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5g) is —OC(O)R^(a), wherein R^(1a) isas defined herein. In certain embodiments, R^(5g) is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R^(5g) is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5g) is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5g) is —OS(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(5g) is —OS(O)₂R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(5g) is—OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments. R^(5g) is —OS(O)₂NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(5g) is —NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5g) is amino (—NH₂). In certainembodiments, R^(5g) is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R^(5g) is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5g) is —NR^(1a)C(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5g) is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), whereinR^(1a), R^(1b), R^(1c), and R^(1d) are each as defined herein. Incertain embodiments, R^(5g) is —NR^(1a)S(O)R^(1d), wherein R^(1a) andR^(1d) are each as defined herein. In certain embodiments, R^(5g) is—NR^(a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(5g) is —NR^(1a)S(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(5g) is —NR^(1a)S(O)₂NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R^(5g) is —SR^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R^(5g) is —S(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(5g) is —S(O)₂R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(5g) is—S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(5g) is —S(O)₂NR^(1b)R^(1c); whereinR^(1b) and R^(1c) are each as defined herein.

In certain embodiments, when one occurrence of R^(5f) and one occurrenceof R^(5g) are attached to the same carbon atom, the R^(5f) and R^(5g)together with the carbon atom to which they are attached form a C₃₋₁₀cycloalkyl, optionally substituted with one or more substituents Q asdescribed herein. In certain embodiments, when one occurrence of R^(5f)and one occurrence of R^(5g) are attached to the same carbon atom, theR^(5f) and R^(5g) together with the carbon atom to which they areattached form a C₃₋₇ cycloalkyl, optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, when oneoccurrence of R^(5f) and one occurrence of R^(5g) are attached to thesame carbon atom, the R^(5f) and R^(5g) together with the carbon atom towhich they are attached form a cyclopropyl, optionally substituted withone or more substituents Q as described herein. In certain embodiments,when one occurrence of R^(5f) and one occurrence of R^(5g) are attachedto the same carbon atom, the R^(5f) and R^(5g) together with the carbonatom to which they are attached form a cyclobutyl, optionallysubstituted with one or more substituents Q as described herein. Incertain embodiments, when one occurrence of R^(5f) and one occurrence ofR^(5g) are attached to the same carbon atom, the R^(5f) and R^(5g)together with the carbon atom to which they are attached form acyclopentyl, optionally substituted with one or more substituents Q asdescribed herein. In certain embodiments, when one occurrence of R^(5f)and one occurrence of R^(5g) are attached to the same carbon atom, theR^(5f) and R^(5g) together with the carbon atom to which they areattached form a cyclohexyl, optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, when oneoccurrence of R^(5f) and one occurrence of R^(5g) are attached to thesame carbon atom, the R^(5f) and R^(5g) together with the carbon atom towhich they are attached form a cycloheptyl, optionally substituted withone or more substituents Q as described herein. In certain embodiments,when one occurrence of R^(5f) and one occurrence of R^(5g) are attachedto the same carbon atom, the R^(5f) and R^(5g) together with the carbonatom to which they are attached form a cyclopropyl

In certain embodiments, when one occurrence of R^(5f) and one occurrenceof R^(5g) are attached to the same carbon atom, the R^(5f) and R^(5g)together with the carbon atom to which they are attached form aheterocyclyl, optionally substituted with one or more substituents Q asdescribed herein. In certain embodiments, when one occurrence of R^(5f)and one occurrence of R^(5g) are attached to the same carbon atom, theR^(5f) and R^(5g) together with the carbon atom to which they areattached form a 3-membered heterocyclyl, optionally substituted with oneor more substituents Q as described herein. In certain embodiments, whenone occurrence of R^(5f) and one occurrence of R^(5g) are attached tothe same carbon atom, the R^(5f) and R^(5g) together with the carbonatom to which they are attached form a 4-membered heterocyclyl,optionally substituted with one or more substituents Q as describedherein. In certain embodiments, when one occurrence of R^(5f) and oneoccurrence of R^(5g) are attached to the same carbon atom, the R^(5f)and R^(5g) together with the carbon atom to which they are attached forma 5-membered heterocyclyl, optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, when oneoccurrence of R^(5f) and one occurrence of R^(5g) are attached to thesame carbon atom, the R^(5f) and R^(5g) together with the carbon atom towhich they are attached form a 6-membered heterocyclyl, optionallysubstituted with one or more substituents Q as described herein.

In certain embodiments, R^(7a) is hydrogen. In certain embodiments,R^(7a) is cyano. In certain embodiments, R^(7a) is halo. In certainembodiments, R^(7a) is fluoro, chloro, bromo, or iodo. In certainembodiments, R^(7a) is nitro. In certain embodiments, R^(7a) is C₁₋₆alkyl, optionally substituted with one or more substituents Q asdescribed herein. In certain embodiments, R^(7a) is C₂₋₆ alkenyl,optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R^(7a) is C₂₋₆ alkynyl, optionallysubstituted with one or more substituents Q as described herein. Incertain embodiments, R^(7a) is C₃₋₇ cycloalkyl, optionally substitutedwith one or more substituents Q as described herein. In certainembodiments, R^(7a) is C₃₋₁₀ cycloalkyl, optionally substituted with oneor more substituents Q as described herein. In certain embodiments,R^(7a) is C₆₋₁₄ aryl, optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, R^(7a) isphenyl, optionally substituted with one or more substituents Q asdescribed herein. In certain embodiments, R^(7a) is phenyl, optionallysubstituted with one or more substituents, each of which is selectedindependently from the group consisting of fluoro, chloro, bromo,methyl, and methoxy. In certain embodiments, R^(7a) is phenyl,2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl. Incertain embodiments, R^(7a) is C₇₋₁₅ aralkyl, optionally substitutedwith one or more substituents Q as described herein. In certainembodiments, R^(7a) is heteroaryl, optionally substituted with one ormore substituents Q as described herein. In certain embodiments, R^(7a)is monocyclic heteroaryl, optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, R^(7a) is5-membered heteroaryl, optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, R^(7a) isimidazolyl or pyrozolyl, optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, R^(7a) isimidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl, or2-methylpyrozol-3-yl. In certain embodiments, R^(7a) is 6-memberedheteroaryl, optionally substituted with one or more substituents Q asdescribed herein. In certain embodiments, R^(7a) is pyridinyl,optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R^(7a) is pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 2-methylpyridin-4-yl, or 2-methoxypyridin-4-yl. In certainembodiments, R^(7a) is heterocyclyl, optionally substituted with one ormore substituents Q as described herein. In certain embodiments, R^(7a)is monocyclic heterocyclyl, optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, R^(7a) is5-membered heterocyclyl, optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, R^(7a) is6-membered heterocyclyl, optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, R^(7a) ispiperidinyl or piperazinyl, optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, R^(7a) is1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl. In certainembodiments, R^(7a) is —C(O)R^(1a), wherein R^(1a) is as defined herein.In certain embodiments, R^(7a) is —C(O)OR^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(7a) is —C(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) is each as defined herein. In certainembodiments, R^(7a) is —C(NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b),and R^(1c) are each as defined herein. In certain embodiments, R^(7a) is—OR^(1a), wherein R^(1a) is as defined herein. In certain embodiments,R¹ is —O—C₂₋₆ alkyl, wherein the alkyl is optionally substituted withone or more substituents Q as described herein. In certain embodiments,R¹ is methoxy, ethoxy, propoxy, isopropoxy, or 3-dimethylaminopropoxy.In certain embodiments, R^(7a) is —OC(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(7a) is —OC(O)OR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(1a) is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(7a) is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(a) is —OS(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(7a) is —OS(O)₂R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(1a) is—OS(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(7a) is —OS(O)₂NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(7a) is —NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(7a) is amino (—NH₂). In certainembodiments, R^(7a) is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R^(7a) is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(7a) is —NR^(1a)C(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(7a) is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), whereinR^(1a),

R^(1b), R^(1c), and R^(1d) are each as defined herein. In certainembodiments, R^(7a) is —NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R^(7a) is—NR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(7a) is —NR^(1a)S(O)NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(7a) is —NR^(1a)S(O)₂NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R^(7a) is —SR^(1a), wherein R^(1a) is as defined herein. Incertain embodiments, R^(7a) is —S(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(7a) is —S(O)₂R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R^(a) is—S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(7a) is —S(O)₂NR^(1b)R^(1c); whereinR^(1b) and R^(1c) are each as defined herein.

In certain embodiments, R^(7a) is phenyl, imidazolyl, pyrozolyl,pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one or more substituents Q. In certainembodiments, R^(7a) is phenyl, 2-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl,3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl,4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3-morpholin-4-ylmethylphenyl, imidazol-1-yl, pyrozol-4-yl,1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments, R^(7b) is hydrogen. In certain embodiments,R^(7b) is cyano. In certain embodiments, R^(7b) is halo. In certainembodiments, R^(7b) is fluoro, chloro, bromo, or iodo. In certainembodiments, R^(7b) is nitro. In certain embodiments, R^(7b) is C₁₋₆alkyl, optionally substituted with one or more substituents Q asdescribed herein. In certain embodiments, R^(7b) is C₂₋₆ alkenyl,optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R^(7b) is C₂₋₆ alkynyl, optionallysubstituted with one or more substituents Q as described herein. Incertain embodiments, R^(7b) is C₃₋₁₀ cycloalkyl, optionally substitutedwith one or more substituents Q as described herein. In certainembodiments, R^(7b) is C₃₋₇ cycloalkyl, optionally substituted with oneor more substituents Q as described herein. In certain embodiments,R^(7b) is C₆₋₁₄ aryl, optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, R^(7b) isC₇₋₁₅ aralkyl, optionally substituted with one or more substituents Q asdescribed herein. In certain embodiments, R^(7b) is heteroaryl,optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R^(7b) is heterocyclyl, optionallysubstituted with one or more substituents Q as described herein.

In certain embodiments, R^(7b) is —C(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(7b) is —C(O)OR^(1a), whereinR^(a) is as defined herein. In certain embodiments, R^(7b) is—C(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(7b) is —C(NR^(1a))NR^(1b)R^(1c),wherein R^(7a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(7b) is —OR^(1a), wherein R^(a) is as definedherein. In certain embodiments, R¹ is —O—C₁₋₆ alkyl, wherein the alkylis optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R¹ is methoxy, ethoxy, propoxy,isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments, R^(7b) is—OC(O)R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R^(7b) is —OC(O)OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(7b) is —OC(O)NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(7b) is —OC(═NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c)are each as defined herein. In certain embodiments, R^(7b) is—OS(O)R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R^(7b) is —OS(O)₂R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(7b) is —OS(O)NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(7b) is —OS(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each asdefined herein. In certain embodiments, R^(7b) is —NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R^(7b) is amino (—NH₂). In certain embodiments, R^(7b) is—NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(7b) is —NR^(1a)C(O)OR^(1d), whereinR^(1a) and R^(1d) are each as defined herein. In certain embodiments,R^(7b) is —NR^(1a)C(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c)are each as defined herein. In certain embodiments, R^(7b) is—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), wherein R^(1a), R^(1b), R^(1c), andR^(1d) are each as defined herein. In certain embodiments, R^(7b) is—NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(7b) is —NR^(1a)S(O)₂R^(1d), whereinR^(1a) and R^(1d) are each as defined herein. In certain embodiments,R^(7b) is —NR^(1a)S(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c)are each as defined herein. In certain embodiments, R^(7b) is—NR^(1a)S(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R^(7b) is —SR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(7b) is—S(O)R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R^(7b) is —S(O)₂R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(7b) is —S(O)NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(7b) is —S(O)₂NR^(1b)R^(1c); wherein R^(1b) and R^(1c) are each asdefined herein.

In certain embodiments, R^(7b) is phenyl, imidazolyl, pyrozolyl,pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one or more substituents Q. In certainembodiments, R^(7b) is phenyl, 2-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl,3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl,4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3-morpholin-4-ylmethylphenyl, imidazol-1-yl, pyrozol-4-yl,1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments, R^(7c) is hydrogen. In certain embodiments,R^(7c) is cyano. In certain embodiments, R^(7c) is halo. In certainembodiments, R^(7c) is fluoro, chloro, bromo, or iodo. In certainembodiments, R^(7c) is nitro. In certain embodiments, R^(7c) is C₁₋₆alkyl, optionally substituted with one or more substituents Q asdescribed herein. In certain embodiments, R^(7c) is C₂₋₆ alkenyl,optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R^(7c) is C₂₋₆ alkynyl, optionallysubstituted with one or more substituents Q as described herein. Incertain embodiments, R^(7c) is C₃₋₁₀ cycloalkyl, optionally substitutedwith one or more substituents Q as described herein. In certainembodiments, R^(7c) is C₃₋₇ cycloalkyl, optionally substituted with oneor more substituents Q as described herein. In certain embodiments,R^(7c) is C₆₋₄ aryl, optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, R^(1c) isC₇₋₁₅ aralkyl, optionally substituted with one or more substituents Q asdescribed herein. In certain embodiments, R^(7c) is heteroaryl,optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R^(7c) is heterocyclyl, optionallysubstituted with one or more substituents Q as described herein.

In certain embodiments, R^(7c) is —C(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(7c) is —C(O)OR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(7c) is—C(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(1c) is —C(NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(7c) is —OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R¹ is —O—C₁₋₆ alkyl, wherein the alkylis optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R¹ is methoxy, ethoxy, propoxy,isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments, R^(7c) is—OC(O)R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R^(7c) is —OC(O)OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(7c) is —OC(O)NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(7c) is —OC(═NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c)are each as defined herein. In certain embodiments, R^(7c) is—OS(O)R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R^(7c) is —OS(O)₂R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(7c) is —OS(O)NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(7c) is —OS(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each asdefined herein. In certain embodiments, R^(7c) is —NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R^(7c) is amino (—NH₂). In certain embodiments, R^(7c) is—NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(7c) is —NR^(1a)C(O)OR^(1d), whereinR^(1a) and R^(1d) are each as defined herein. In certain embodiments,R^(7c) is —NR^(1a)C(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c)are each as defined herein. In certain embodiments, R^(7c) is—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), wherein R^(1a), R^(1b), R^(1c), andR^(1d) are each as defined herein. In certain embodiments, R^(7c) is—NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(7c) is —NR^(1a)S(O)₂R^(1d), whereinR^(1a) and R^(1d) are each as defined herein. In certain embodiments,R^(7c) is —NR^(1a)S(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c)are each as defined herein. In certain embodiments, R^(7c) is—NR^(1a)S(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R^(7c) is —SR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(7c) is—S(O)R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R^(7c) is —S(O)₂R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(7c) is —S(O)NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(7c) is —S(O)₂NR^(1b)R^(1c); wherein R^(1b) and R^(1c) are each asdefined herein.

In certain embodiments, R^(7c) is phenyl, imidazolyl, pyrozolyl,pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one or more substituents Q. In certainembodiments, R^(7c) is phenyl, 2-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl,3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl,4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3-morpholin-4-ylmethylphenyl, imidazol-1-yl, pyrozol-4-yl,1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments, R^(7d) is hydrogen. In certain embodiments,R^(7d) is cyano. In certain embodiments, R^(7d) is halo. In certainembodiments, R^(7d) is fluoro, chloro, bromo, or iodo. In certainembodiments, R^(7d) is nitro. In certain embodiments, R^(7d) is C₁₋₆alkyl, optionally substituted with one or more substituents Q asdescribed herein. In certain embodiments, R^(7d) is C₂₋₆ alkenyl,optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R^(7d) is C₂₋₆ alkynyl, optionallysubstituted with one or more substituents Q as described herein. Incertain embodiments, R^(7d) is C₃₋₁₀ cycloalkyl, optionally substitutedwith one or more substituents Q as described herein. In certainembodiments, R^(7d) is C₃₋₇ cycloalkyl, optionally substituted with oneor more substituents Q as described herein. In certain embodiments,R^(7d) is C₆₋₁₄ aryl, optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, R^(7d) isC₇₋₁₅ aralkyl, optionally substituted with one or more substituents Q asdescribed herein. In certain embodiments, R^(7d) is heteroaryl,optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R^(7d) is heterocyclyl, optionallysubstituted with one or more substituents Q as described herein.

In certain embodiments, R^(7d) is —C(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(7d) is —C(O)OR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(7d) is—C(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(7d) is —C(NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(7d) is —OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R¹ is —O—C₁₋₆ alkyl, wherein the alkylis optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R¹ is methoxy, ethoxy, propoxy,isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments, R^(7d) is—OC(O)R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R^(7d) is —OC(O)OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(7d) is —OC(O)NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(7d) is —OC(═NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c)are each as defined herein. In certain embodiments, R^(5d) is—OS(O)R^(1b), wherein R^(1a) is as defined herein. In certainembodiments, R^(7d) is —OS(O)₂R^(7a), wherein R^(1a) is as definedherein. In certain embodiments, R^(7d) is —OS(O)NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(7d) is —OS(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each asdefined herein. In certain embodiments, R^(7d) is —NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R^(7d) is amino (—NH₂). In certain embodiments, R^(7d) is—NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(7d) is —NR^(1a)C(O)OR^(1d), whereinR^(1a) and R^(1d) are each as defined herein. In certain embodiments,R^(7d) is —NR^(1a)C(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c)are each as defined herein. In certain embodiments, R^(7d) is—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), wherein R^(1a), R^(1b), R^(1c), andR^(1d) are each as defined herein. In certain embodiments, R^(7d) is—NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(7d) is —NR^(1a)S(O)₂R^(1d), whereinR^(1a) and R^(1d) are each as defined herein. In certain embodiments,R^(7d) is —NR^(1a)S(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c)are each as defined herein. In certain embodiments, R^(7d) is—NR^(1a)S(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R^(7d) is —SR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(7d) is—S(O)R^(a), wherein R^(1a) is as defined herein. In certain embodiments,R^(7d) is —S(O)₂R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R^(7d) is —S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R^(7d) is—S(O)₂NR^(1b)R^(1c); wherein R^(1b) and R^(1c) are each as definedherein.

In certain embodiments, R^(7d) is phenyl, imidazolyl, pyrozolyl,pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one or more substituents Q. In certainembodiments, R^(7d) is phenyl, 2-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl,3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl,4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3-morpholin-4-ylmethylphenyl, imidazol-1-yl, pyrozol-4-yl,1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments, R^(7e) is hydrogen. In certain embodiments,R^(7e) is cyano. In certain embodiments, R^(7e) is halo. In certainembodiments, R^(7e) is fluoro, chloro, bromo, or iodo. In certainembodiments, R^(7e) is nitro. In certain embodiments, R^(7e) is C₁₋₆alkyl, optionally substituted with one or more substituents Q asdescribed herein. In certain embodiments, R^(7e) is C₂₋₆ alkenyl,optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R^(7e) is C₂₋₆ alkynyl, optionallysubstituted with one or more substituents Q as described herein. Incertain embodiments, R^(7e) is C₃₋₁₀ cycloalkyl, optionally substitutedwith one or more substituents Q as described herein. In certainembodiments, R^(7e) is C₃₋₇ cycloalkyl, optionally substituted with oneor more substituents Q as described herein. In certain embodiments,R^(7e) is C₆₋₁₄ aryl, optionally substituted with one or moresubstituents Q as described herein. In certain embodiments, R^(7e) isC₇₋₁₅ aralkyl, optionally substituted with one or more substituents Q asdescribed herein. In certain embodiments, R^(7e) is heteroaryl,optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R^(7e) is heterocyclyl, optionallysubstituted with one or more substituents Q as described herein.

In certain embodiments, R^(7e) is —C(O)R^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R^(7e) is —C(O)OR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(7e) is—C(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R^(7e) is —C(NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R^(7e) is —OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R¹ is —O—C₁₋₆ alkyl, wherein the alkylis optionally substituted with one or more substituents Q as describedherein. In certain embodiments, R¹ is methoxy, ethoxy, propoxy,isopropoxy, or 3-dimethylaminopropoxy. In certain embodiments, R^(7c) is—OC(O)R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R^(7e) is —OC(O)OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(7e) is —OC(O)NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(7e) is —OC(═NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c)are each as defined herein. In certain embodiments, R^(7e) is—OS(O)R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R^(7e) is —OS(O)₂R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(7e) is —OS(O)NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(7e) is —OS(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each asdefined herein. In certain embodiments, R^(7e) is —NR^(1b)R^(c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(7e) is amino (—NH₂). In certain embodiments, R^(7e) is—NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(7e) is —NR^(1a)C(O)OR^(1d), whereinR^(1a) and R^(1d) are each as defined herein. In certain embodiments,R^(7e) is —NR^(1a)C(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c)are each as defined herein. In certain embodiments, R^(7e) is—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), wherein R^(1a), R^(1b), R^(1c), andR^(1d) are each as defined herein. In certain embodiments, R^(7c) is—NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R^(e) is —NR^(1a)S(O)₂R^(1d), whereinR^(1a) and R^(1d) are each as defined herein. In certain embodiments,R^(7e) is —NR^(1a)S(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c)are each as defined herein. In certain embodiments, R^(7e) is—NR^(1a)S(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R^(e) is —SR^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R^(7e) is—S(O)R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R^(7e) is —S(O)₂R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R^(7e) is —S(O)NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein. In certain embodiments,R^(7c) is —S(O)₂NR^(1b)R^(1c); wherein R^(1b) and R^(1c) are each asdefined herein.

In certain embodiments, R^(7e) is phenyl, imidazolyl, pyrozolyl,pyridinyl, pyrimidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, eachoptionally substituted with one or more substituents Q. In certainembodiments, R^(7e) is phenyl, 2-fluorophenyl, 2-chlorophenyl,2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl,2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl,3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl,4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,4-fluoro-3-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3-morpholin-4-ylmethylphenyl, imidazol-1-yl, pyrozol-4-yl,1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl,2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl,pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl,1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl,1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In certain embodiments, R^(7a) and R^(7b) together with the carbon atomsto which they are attached form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each optionally substituted with one ormore substituents Q. In certain embodiments, R^(7a) and R^(7b) togetherwith the carbon atoms to which they are attached form C₃₋₁₀cycloalkenyl, optionally substituted with one or more substituents Q. Incertain embodiments, R^(7a) and R^(7b) together with the carbon atoms towhich they are attached form cyclohexenyl, optionally substituted withone or more substituents Q. In certain embodiments, R^(7a) and R^(7b)together with the carbon atoms to which they are attached form C₆₋₁₄aryl, optionally substituted with one or more substituents Q. In certainembodiments, R^(7a) and R^(7b) together with the carbon atoms to whichthey are attached form phenyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R^(7a) and R^(7b) together withthe carbon atoms to which they are attached form heteroaryl, optionallysubstituted with one or more substituents Q. In certain embodiments,R^(7a) and R^(7b) together with the carbon atoms to which they areattached form monocyclic heteroaryl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(7a) and R^(7b) togetherwith the carbon atoms to which they are attached form 5- or 6-memberedheteroaryl, optionally substituted with one or more substituents Q. Incertain embodiments, R^(7a) and R^(7b) together with the carbon atoms towhich they are attached form bicyclic heteroaryl, optionally substitutedwith one or more substituents Q. In certain embodiments, R^(7a) andR^(7b) together with the carbon atoms to which they are attached formheterocyclyl, optionally substituted with one or more substituents Q. Incertain embodiments, R^(7a) and R^(7b) together with the carbon atoms towhich they are attached form monocyclic heterocyclyl, optionallysubstituted with one or more substituents Q. In certain embodiments,R^(7a) and R^(7b) together with the carbon atoms to which they areattached form 5- or 6-membered heterocyclyl, optionally substituted withone or more substituents Q. In certain embodiments, R^(7a) and R^(7b)together with the carbon atoms to which they are attached form bicyclicheterocyclyl, optionally substituted with one or more substituents Q.

In certain embodiments, R^(7b) and R^(7c) together with the carbon atomsto which they are attached form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each optionally substituted with one ormore substituents Q. In certain embodiments, R^(7b) and R^(7c) togetherwith the carbon atoms to which they are attached form C₃₋₁₀cycloalkenyl, optionally substituted with one or more substituents Q. Incertain embodiments, R^(7b) and R^(7c) together with the carbon atoms towhich they are attached form cyclohexenyl, optionally substituted withone or more substituents Q. In certain embodiments, R^(7b) and R^(7c)together with the carbon atoms to which they are attached form C₆₋₁₄aryl, optionally substituted with one or more substituents Q. In certainembodiments, R^(7b) and R^(7c) together with the carbon atoms to whichthey are attached form phenyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R^(7b) and R^(7c) together withthe carbon atoms to which they are attached form heteroaryl, optionallysubstituted with one or more substituents Q. In certain embodiments,R^(7b) and R^(7c) together with the carbon atoms to which they areattached form monocyclic heteroaryl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(7b) and R^(7c) togetherwith the carbon atoms to which they are attached form 5- or 6-memberedheteroaryl, optionally substituted with one or more substituents Q. Incertain embodiments, R^(7b) and R^(7c) together with the carbon atoms towhich they are attached form bicyclic heteroaryl, optionally substitutedwith one or more substituents Q. In certain embodiments, R^(7b) andR^(7c) together with the carbon atoms to which they are attached formheterocyclyl, optionally substituted with one or more substituents Q. Incertain embodiments, R^(7b) and R^(7c) together with the carbon atoms towhich they are attached form monocyclic heterocyclyl, optionallysubstituted with one or more substituents Q. In certain embodiments,R^(7b) and R^(7c) together with the carbon atoms to which they areattached form 5- or 6-membered heterocyclyl, optionally substituted withone or more substituents Q. In certain embodiments, R^(7b) and R^(7c)together with the carbon atoms to which they are attached form bicyclicheterocyclyl, optionally substituted with one or more substituents Q.

In certain embodiments, R^(7c) and R^(7d) together with the carbon atomsto which they are attached form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each optionally substituted with one ormore substituents Q. In certain embodiments, R^(7c) and R^(7d) togetherwith the carbon atoms to which they are attached form C₃₋₁₀cycloalkenyl, optionally substituted with one or more substituents Q. Incertain embodiments, R^(7c) and R^(7d) together with the carbon atoms towhich they are attached form cyclohexenyl, optionally substituted withone or more substituents Q. In certain embodiments, R^(7c) and R^(7d)together with the carbon atoms to which they are attached form C₆₋₁₄aryl, optionally substituted with one or more substituents Q. In certainembodiments, R^(7c) and R^(7d) together with the carbon atoms to whichthey are attached form phenyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R^(7c) and R^(7d) together withthe carbon atoms to which they are attached form heteroaryl, optionallysubstituted with one or more substituents Q. In certain embodiments,R^(7c) and R^(7d) together with the carbon atoms to which they areattached form monocyclic heteroaryl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(7c) and R^(7d) togetherwith the carbon atoms to which they are attached form 5- or 6-memberedheteroaryl, optionally substituted with one or more substituents Q. Incertain embodiments, R^(7c) and R^(7d) together with the carbon atoms towhich they are attached form bicyclic heteroaryl, optionally substitutedwith one or more substituents Q. In certain embodiments, R^(7c) andR^(7d) together with the carbon atoms to which they are attached formheterocyclyl, optionally substituted with one or more substituents Q. Incertain embodiments, R^(7c) and R^(7d) together with the carbon atoms towhich they are attached form monocyclic heterocyclyl, optionallysubstituted with one or more substituents Q. In certain embodiments,R^(7c) and R^(7d) together with the carbon atoms to which they areattached form 5- or 6-membered heterocyclyl, optionally substituted withone or more substituents Q. In certain embodiments, R^(7c) and R^(7d)together with the carbon atoms to which they are attached form bicyclicheterocyclyl, optionally substituted with one or more substituents Q.

In certain embodiments, R^(7d) and R^(7e) together with the carbon atomsto which they are attached form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl,heteroaryl, or heterocyclyl, each optionally substituted with one ormore substituents Q. In certain embodiments, R^(7d) and R^(7e) togetherwith the carbon atoms to which they are attached form C₃₋₁₀cycloalkenyl, optionally substituted with one or more substituents Q. Incertain embodiments, R^(7d) and R^(7e) together with the carbon atoms towhich they are attached form cyclohexenyl, optionally substituted withone or more substituents Q. In certain embodiments, R^(7d) and R^(7c)together with the carbon atoms to which they are attached form C₆₋₁₄aryl, optionally substituted with one or more substituents Q. In certainembodiments, R^(7d) and R^(7e) together with the carbon atoms to whichthey are attached form phenyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R^(7d) and R^(7e) together withthe carbon atoms to which they are attached form heteroaryl, optionallysubstituted with one or more substituents Q. In certain embodiments,R^(7d) and R^(7e) together with the carbon atoms to which they areattached form monocyclic heteroaryl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(7d) and R^(7e) togetherwith the carbon atoms to which they are attached form 5- or 6-memberedheteroaryl, optionally substituted with one or more substituents Q. Incertain embodiments, R^(7d) and R^(7e) together with the carbon atoms towhich they are attached form bicyclic heteroaryl, optionally substitutedwith one or more substituents Q. In certain embodiments, R^(7d) andR^(7e) together with the carbon atoms to which they are attached formheterocyclyl, optionally substituted with one or more substituents Q. Incertain embodiments, R^(7d) and R^(7e) together with the carbon atoms towhich they are attached form monocyclic heterocyclyl, optionallysubstituted with one or more substituents Q. In certain embodiments,R^(7d) and R^(7e) together with the carbon atoms to which they areattached form 5- or 6-membered heterocyclyl, optionally substituted withone or more substituents Q. In certain embodiments, R^(7d) and R^(7e)together with the carbon atoms to which they are attached form bicyclicheterocyclyl, optionally substituted with one or more substituents Q.

In certain embodiments, m is 0. In certain embodiments, m is 1.

In certain embodiments, n is 0. In certain embodiments, n is 1. Incertain embodiments, n is 2. In certain embodiments, n is 3. In certainembodiments, n is 4. In certain embodiments, n is 0, 1, or 2. In certainembodiments, n is 0, 1, 2, or 3. In certain embodiments, n is 1, 2, or3. In certain embodiments, n is 1 or 2.

In certain embodiments, m is 0, and n is 0, 1, 2, or 3. In certainembodiments, m is 0, n is 0, 1, or 2. In certain embodiments, m is 0, nis 0 or 1. In certain embodiments, m is 0, n is 0. In certainembodiments, m is 0, n is 1. In certain embodiments, m is 1, n is 0, 1,2, or 3. In certain embodiments, m is 1, n is 0, 1, or 2. In certainembodiments, m is 1, n is 0 or 1. In certain embodiments, m is 1, n is0. In certain embodiments, m is 1, n is 1.

In specific embodiments, m is 0, n is 1, and R^(5a) and R^(5b) are eachmethyl.

In certain embodiments, X is N. In certain embodiments, X is CR^(x),wherein R^(x) is as defined herein. In certain embodiments, X is CH.

In certain embodiments, Y is N. In certain embodiments, Y is CR^(x),wherein R^(x) is as defined herein. In certain embodiments, Y is CH.

In certain embodiments, Z is N. In certain embodiments, Z is CR^(x),wherein R^(x) is as defined herein. In certain embodiments, Z is CH.

In certain embodiments, X, Y, and Z are N. In certain embodiments, X andY are N, and Z is CH. In certain embodiments, X and Z are N, and Y isCH. In certain embodiments, Y and Z are N, and X is CH.

In certain embodiments, the compound provided herein is not4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-N-(2-phenyl-2-(pyrrolidin-1-yl)ethyl)-1,3,5-triazin-2-amine.In certain embodiments, the compound provided herein is not6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(4-((R)-3-(methoxymethyl)morpholino)phenyl)ethyl)-2-morpholinopyrimidin-4-amine.

In certain embodiments, when X, Y, and Z are N, and R^(5a) is hydrogen,R^(5b) is not heterocyclyl. In certain embodiments, when X, Y, and Z areN, and R^(5a) is hydrogen, R^(5b) is not 5-membered heterocyclyl. Incertain embodiments, when X, Y, and Z are N, and R^(5a) is hydrogen,R^(5b) is not pyrrolidinyl. In certain embodiments, when X, Y, and Z areN, and R^(5a) is hydrogen, R^(5b) is not pyrrolidin-1-yl.

In certain embodiments, when X and Z are N, Y is CH, and R^(5a) ishydrogen, R^(5b) is morpholino-substituted phenyl. In certainembodiments, when X and Z are N, Y is CH, and R^(5a) is hydrogen, R^(5b)is not 4-((R)-3-(methoxymethyl)morpholino)phenyl.

In one embodiment, provided herein is a compound selected from:

and enantiomers, mixtures of enantiomers, mixtures of two or morediastereomers, and isotopic variants thereof; and pharmaceuticallyacceptable salts, solvates, hydrates, and prodrugs thereof.

The compounds provided herein are intended to encompass all possiblestereoisomers, unless a particular stereochemistry is specified. Wherethe compound provided herein contains an alkenyl or alkenylene group,the compound may exist as one or mixture of geometric cis/trans (or Z/E)isomers. Where structural isomers are interconvertible, the compound mayexist as a single tautomer or a mixture of tautomers. This can take theform of proton tautomerism in the compound that contains, for example,an imino, keto, or oxime group; or so-called valence tautomerism in thecompound that contain an aromatic moiety. It follows that a singlecompound may exhibit more than one type of isomerism.

The compounds provided herein may be enantiomerically pure, such as asingle enantiomer or a single diastereomer, or be stereoisomericmixtures, such as a mixture of enantiomers, e.g., a racemic mixture oftwo enantiomers; or a mixture of two or more diastereomers. As such, oneof skill in the art will recognize that administration of a compound inits (R) form is equivalent, for compounds that undergo epimerization invivo, to administration of the compound in its (S) form. Conventionaltechniques for the preparation/isolation of individual enantiomersinclude synthesis from a suitable optically pure precursor, asymmetricsynthesis from achiral starting materials, or resolution of anenantiomeric mixture, for example, chiral chromatography,recrystallization, resolution, diastereomeric salt formation, orderivatization into diastereomeric adducts followed by separation.

When the compound provided herein contains an acidic or basic moiety, itmay also be provided as a pharmaceutically acceptable salt (See, Bergeet al., J. Pharm. Sci. 1977, 66, 1-19; and “Handbook of PharmaceuticalSalts, Properties, and Use,” Stahl and Wermuth, Ed.; Wiley-VCH and VHCA,Zurich, 2002).

Suitable acids for use in the preparation of pharmaceutically acceptablesalts include, but are not limited to, acetic acid, 2,2-dichloroaceticacid, acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, boric acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid,D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid,hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid,(+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid,maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid,methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, andvaleric acid.

Suitable bases for use in the preparation of pharmaceutically acceptablesalts, including, but not limited to, inorganic bases, such as magnesiumhydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, orsodium hydroxide; and organic bases, such as primary, secondary,tertiary, and quaternary, aliphatic and aromatic amines, includingL-arginine, benethamine, benzathine, choline, deanol, diethanolamine,diethylamine, dimethylamine, dipropylamine, diisopropylamine,2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine,isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine,morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine,piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine,pyridine, quinuclidine, quinoline, isoquinoline, secondary amines,triethanolamine, trim ethylamine, triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

The compound provided herein may also be provided as a prodrug, which isa functional derivative of the compound, for example, of Formula I, andis readily convertible into the parent compound in vivo. Prodrugs areoften useful because, in some situations, they may be easier toadminister than the parent compound. They may, for instance, bebioavailable by oral administration whereas the parent compound is not.The prodrug may also have enhanced solubility in pharmaceuticalcompositions over the parent compound. A prodrug may be converted intothe parent drug by various mechanisms, including enzymatic processes andmetabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4,221-294; Morozowich et al. in “Design of Biopharmaceutical Propertiesthrough Prodrugs and Analogs,” Roche Ed., APHA Acad. Pharm. Sci. 1977:“Bioreversible Carriers in Drug in Drug Design, Theory and Application,”Roche Ed., APHA Acad. Pharm. Sci. 1987; “Design of Prodrugs,” Bundgaard,Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265-287;Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen etal., Pharm. Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med.Chem. 1996, 671-696; Asgharnejad in “Transport Processes inPharmaceutical Systems,” Amidon et al., Ed., Marcell Dekker, 185-218,2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15,143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209;Browne, Clin. Neuropharmcol. 1997, 20, 1-12; Bundgaard, Arch. Pharm.Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17,179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher etal., Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al., MethodsEnzymol. 1985, 112, 360-381; Farquhar et al., J. Pharm. Sci. 1983, 72,324-325; Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875-877;Friis and Bundgaard, Eur. J. Pharm. Sci. 1996,4, 49-59; Gangwar et al.,Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood,Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev.1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et al.,Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug DeliveryRev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999,39,63-80; and Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507.

Methods of Synthesis

The compound provided herein can be prepared, isolated, or obtained byany method known to one of skill in the art, and the following examplesare only representative and do not exclude other related procedures.

In one embodiment, for example, a compound of Formula I can be prepared,as shown in Scheme I, via a first aromatic substitution reaction of atrihalo-substituted triazine or pyrimidine with compound 1-1 to formcompound 1-2, which can subsequently be converted to compound I-4 via asecond aromatic substitution reaction with compound I-3. Compound 1-4can then be converted to a compound of Formula I via a third aromaticsubstitution reaction with NH₂(CR^(5d)R^(5e))_(m)C(R^(5a)R^(5b)R^(5c)).

In one embodiment, for example, a compound of Formula II can beprepared, as shown in Scheme II, via a first aromatic substitutionreaction of a trihalo-substituted triazine or pyrimidine with compoundI-1 to form compound I-2, which can subsequently be converted tocompound I-4 via a second aromatic substitution reaction with compoundI-3. Compound 1-4 can then be converted to a compound of Formula II viaa third aromatic substitution reaction with NH₂C(R^(5a)R^(5b)R^(5c)).

Pharmaceutical Compositions

In one embodiment, provided herein is a pharmaceutical compositioncomprising a compound of Formula I, or an enantiomer, a mixture ofenantiomers, a mixture of two or more diastereomers, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof, and a pharmaceutically acceptableexcipient, adjuvant, carrier, buffer, or stabiliser.

In one embodiment, the pharmaceutical compositions are provided in adosage form for oral administration, which comprise a compound providedherein, and one or more pharmaceutically acceptable excipients orcarriers. The pharmaceutical compositions provided herein that areformulated for oral administration may be in tablet, capsule, powder, orliquid form. A tablet may comprise a solid carrier or an adjuvant.Liquid pharmaceutical compositions generally comprise a liquid carriersuch as water, petroleum, animal or vegetable oils, mineral oil, orsynthetic oil. Physiological saline solution, dextrose or othersaccharide solution, or glycols such as ethylene glycol, propyleneglycol, or polyethylene glycol may be included. A capsule may comprise asolid carrier such as gelatin.

In another embodiment, the pharmaceutical compositions are provided in adosage form for parenteral administration, which comprise a compoundprovided herein, and one or more pharmaceutically acceptable excipientsor carriers. Where pharmaceutical compositions may be formulated forintravenous, cutaneous or subcutaneous injection, the active ingredientwill be in the form of a parenterally acceptable aqueous solution, whichis pyrogen-free and has a suitable pH, isotonicity, and stability. Thoseof relevant skill in the art are well able to prepare suitable solutionsusing, for example, isotonic vehicles, such as Sodium Chlorideinjection, Ringer's injection, or Lactated Ringer's injection.Preservatives, stabilisers, buffers, antioxidants, and/or otheradditives may be included as required.

In yet another embodiment, the pharmaceutical compositions are providedin a dosage form for topical administration, which comprise a compoundprovided herein, and one or more pharmaceutically acceptable excipientsor carriers.

The pharmaceutical compositions can also be formulated as modifiedrelease dosage forms, including delayed-, extended-, prolonged-,sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, andprogrammed-release, and gastric retention dosage forms. These dosageforms can be prepared according to conventional methods and techniquesknown to those skilled in the art (see, Remington: The Science andPractice of Pharmacy, supra; Modified-Release Drug Delivery Technology,2nd Edition, Rathbone et al., Eds., Marcel Dekker, Inc.: New York, N.Y.,2008).

The pharmaceutical compositions provided herein can be provided in aunit-dosage form or multiple-dosage form. A unit-dosage form, as usedherein, refers to physically discrete a unit suitable for administrationto a human and animal subject, and packaged individually as is known inthe art. Each unit-dose contains a predetermined quantity of an activeingredient(s) sufficient to produce the desired therapeutic effect, inassociation with the required pharmaceutical carriers or excipients.Examples of a unit-dosage form include an ampoule, syringe, andindividually packaged tablet and capsule. A unit-dosage form may beadministered in fractions or multiples thereof. A multiple-dosage formis a plurality of identical unit-dosage forms packaged in a singlecontainer to be administered in segregated unit-dosage form. Examples ofa multiple-dosage form include a vial, bottle of tablets or capsules, orbottle of pints or gallons.

The pharmaceutical compositions provided herein can be administered atonce, or multiple times at intervals of time. It is understood that theprecise dosage and duration of treatment may vary with the age, weight,and condition of the patient being treated, and may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test or diagnostic data. It is further understood thatfor any particular individual, specific dosage regimens should beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the formulations.

In certain embodiments, the pharmaceutical compositions provided hereinfurther comprise one or more chemotherapeutic agents as defined herein.

A. Oral Administration

The pharmaceutical compositions provided herein for oral administrationcan be provided in solid, semisolid, or liquid dosage forms for oraladministration. As used herein, oral administration also includesbuccal, lingual, and sublingual administration. Suitable oral dosageforms include, but are not limited to, tablets, fastmelts, chewabletablets, capsules, pills, strips, troches, lozenges, pastilles, cachets,pellets, medicated chewing gum, bulk powders, effervescent ornon-effervescent powders or granules, oral mists, solutions, emulsions,suspensions, wafers, sprinkles, elixirs, and syrups. In addition to theactive ingredient(s), the pharmaceutical compositions can contain one ormore pharmaceutically acceptable carriers or excipients, including, butnot limited to, binders, fillers, diluents, disintegrants, wettingagents, lubricants, glidants, coloring agents, dye-migration inhibitors,sweetening agents, flavoring agents, emulsifying agents, suspending anddispersing agents, preservatives, solvents, non-aqueous liquids, organicacids, and sources of carbon dioxide.

Binders or granulators impart cohesiveness to a tablet to ensure thetablet remaining intact after compression. Suitable binders orgranulators include, but are not limited to, starches, such as cornstarch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500);gelatin; sugars, such as sucrose, glucose, dextrose, molasses, andlactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage ofisabgol husks, carboxymethylcellulose, methylcellulose,polyvinylpynolidone (PVP), Veegum, larch arabogalactan, powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose, celluloseacetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC);microcry stalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103,AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixturesthereof. Suitable fillers include, but are not limited to, talc, calciumcarbonate, microcry stalline cellulose, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizedstarch, and mixtures thereof. The amount of a binder or filler in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The binder or filler may be present from about 50 to about 99%by weight in the pharmaceutical compositions provided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose,kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, andinositol, when present in sufficient quantity, can impart properties tosome compressed tablets that permit disintegration in the mouth bychewing. Such compressed tablets can be used as chewable tablets. Theamount of a diluent in the pharmaceutical compositions provided hereinvaries upon the type of formulation, and is readily discernible to thoseof ordinary skill in the art.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate; microcrystalline cellulose,such as sodium starch glycolate; polacrilin potassium; starches, such ascorn starch, potato starch, tapioca starch, and pre-gelatinized starch;clays; aligns; and mixtures thereof. The amount of a disintegrant in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The amount of a disintegrant in the pharmaceutical compositionsprovided herein varies upon the type of formulation, and is readilydiscernible to those of ordinary skill in the art. The pharmaceuticalcompositions provided herein may contain from about 0.5 to about 15% orfrom about 1 to about 5% by weight of a disintegrant.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;mannitol; glycols, such as glycerol behenate and polyethylene glycol(PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetableoil, including peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyllaureate; agar; starch; lycopodium; silica or silica gels, such asAEROSIOL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co.of Boston, Mass.); and mixtures thereof. The pharmaceutical compositionsprovided herein may contain about 0.1 to about 5% by weight of alubricant.

Suitable glidants include, but are not limited to, colloidal silicondioxide, CAB-O-SIL® (Cabot Co. of Boston, Mass.), and asbestos-freetalc. Suitable coloring agents include, but are not limited to, any ofthe approved, certified, water soluble FD&C dyes, and water insolubleFD&C dyes suspended on alumina hydrate, and color lakes and mixturesthereof. A color lake is the combination by adsorption of awater-soluble dye to a hydrous oxide of a heavy metal, resulting in aninsoluble form of the dye. Suitable flavoring agents include, but arenot limited to, natural flavors extracted from plants, such as fruits,and synthetic blends of compounds which produce a pleasant tastesensation, such as peppermint and methyl salicylate. Suitable sweeteningagents include, but are not limited to, sucrose, lactose, mannitol,syrups, glycerin, and artificial sweeteners, such as saccharin andaspartame. Suitable emulsifying agents include, but are not limited to,gelatin, acacia, tragacanth, bentonite, and surfactants, such aspolyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylenesorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitablesuspending and dispersing agents include, but are not limited to, sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodiumcarbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrrolidone. Suitable preservatives include, but are notlimited to, glycerin, methyl and propylparaben, benzoic add, sodiumbenzoate and alcohol. Suitable wetting agents include, but are notlimited to, propylene glycol monostearate, sorbitan monooleate,diethylene glycol monolaurate, and polyoxyethylene lauryl ether.Suitable solvents include, but are not limited to, glycerin, sorbitol,ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized inemulsions include, but are not limited to, mineral oil and cottonseedoil. Suitable organic acids include, but are not limited to, citric andtartaric acid. Suitable sources of carbon dioxide include, but are notlimited to, sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serveseveral functions, even within the same formulation.

The pharmaceutical compositions provided herein for oral administrationcan be provided as compressed tablets, tablet triturates, chewablelozenges, rapidly dissolving tablets, multiple compressed tablets, orenteric-coating tablets, sugar-coated, or film-coated tablets.Enteric-coated tablets are compressed tablets coated with substancesthat resist the action of stomach acid but dissolve or disintegrate inthe intestine, thus protecting the active ingredients from the acidicenvironment of the stomach. Enteric-coatings include, but are notlimited to, fatty acids, fats, phenyl salicylate, waxes, shellac,ammoniated shellac, and cellulose acetate phthalates. Sugar-coatedtablets are compressed tablets surrounded by a sugar coating, which maybe beneficial in covering up objectionable tastes or odors and inprotecting the tablets from oxidation. Film-coated tablets arecompressed tablets that are covered with a thin layer or film of awater-soluble material. Film coatings include, but are not limited to,hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000, and cellulose acetate phthalate. Film coating imparts thesame general characteristics as sugar coating. Multiple compressedtablets are compressed tablets made by more than one compression cycle,including layered tablets, and press-coated or dry-coated tablets.

The tablet dosage forms can be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein for oral administrationcan be provided as soft or hard capsules, which can be made fromgelatin, methylcellulose, starch, or calcium alginate. The hard gelatincapsule, also known as the dry-filled capsule (DFC), consists of twosections, one slipping over the other, thus completely enclosing theactive ingredient. The soft elastic capsule (SEC) is a soft, globularshell, such as a gelatin shell, which is plasticized by the addition ofglycerin, sorbitol, or a similar poly ol. The soft gelatin shells maycontain a preservative to prevent the growth of microorganisms. Suitablepreservatives are those as described herein, including methyl- andpropyl-parabens, and sorbic acid. The liquid, semisolid, and soliddosage forms provided herein may be encapsulated in a capsule. Suitableliquid and semisolid dosage forms include solutions and suspensions inpropylene carbonate, vegetable oils, or triglycerides. Capsulescontaining such solutions can be prepared as described in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient.

The pharmaceutical compositions provided herein for oral administrationcan be provided in liquid and semisolid dosage forms, includingemulsions, solutions, suspensions, elixirs, and syrups. An emulsion is atwo-phase system, in which one liquid is dispersed in the form of smallglobules throughout another liquid, which can be oil-in-water orwater-in-oil. Emulsions may include a pharmaceutically acceptablenon-aqueous liquid or solvent, emulsifying agent, and preservative.Suspensions may include a pharmaceutically acceptable suspending agentand preservative. Aqueous alcoholic solutions may include apharmaceutically acceptable acetal, such as a di(lower alkyl) acetal ofa lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and awater-miscible solvent having one or more hydroxyl groups, such aspropylene glycol and ethanol. Elixirs are clear, sweetened, andhydroalcoholic solutions. Syrups are concentrated aqueous solutions of asugar, for example, sucrose, and may also contain a preservative. For aliquid dosage form, for example, a solution in a polyethylene glycol maybe diluted with a sufficient quantity of a pharmaceutically acceptableliquid carrier, e.g., water, to be measured conveniently foradministration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations can further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administrationcan be also provided in the forms of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein for oral administrationcan be provided as non-effervescent or effervescent, granules andpowders, to be reconstituted into a liquid dosage form. Pharmaceuticallyacceptable carriers and excipients used in the non-effervescent granulesor powders may include diluents, sweeteners, and wetting agents.Pharmaceutically acceptable carriers and excipients used in theeffervescent granules or powders may include organic acids and a sourceof carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

The pharmaceutical compositions provided herein for oral administrationcan be formulated as immediate or modified release dosage forms,including delayed-, sustained, pulsed-, controlled, targeted-, andprogrammed-release forms.

B. Parenteral Administration

The pharmaceutical compositions provided herein can be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, intravesical, and subcutaneousadministration.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated in any dosage forms that are suitablefor parenteral administration, including solutions, suspensions,emulsions, micelles, liposomes, microspheres, nanosystems, and solidforms suitable for solutions or suspensions in liquid prior toinjection. Such dosage forms can be prepared according to conventionalmethods known to those skilled in the art of pharmaceutical science(see, Remington: The Science and Practice of Pharmacy, supra).

The pharmaceutical compositions intended for parenteral administrationcan include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Suitable non-aqueous vehicles include, but are not limited to, fixedoils of vegetable origin, castor oil, corn oil, cottonseed oil, oliveoil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Suitable water-misciblevehicles include, but are not limited to, ethanol, 1,3-butanediol,liquid polyethylene glycol (e.g., polyethylene glycol 300 andpolyethylene glycol 400), propylene glycol, glycerin,N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride(e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbicacid. Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfite and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsare those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including α-cyclodextrin, β-cyclodextrin,hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, andsulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

When the pharmaceutical compositions provided herein are formulated formultiple dosage administration, the multiple dosage parenteralformulations must contain an antimicrobial agent at bacteriostatic orfungistatic concentrations. All parenteral formulations must be sterile,as known and practiced in the art.

In one embodiment, the pharmaceutical compositions for parenteraladministration are provided as ready-to-use sterile solutions. Inanother embodiment, the pharmaceutical compositions are provided assterile dry soluble products, including lyophilized powders andhypodermic tablets, to be reconstituted with a vehicle prior to use. Inyet another embodiment, the pharmaceutical compositions are provided asready-to-use sterile suspensions. In yet another embodiment, thepharmaceutical compositions are provided as sterile dry insolubleproducts to be reconstituted with a vehicle prior to use. In stillanother embodiment, the pharmaceutical compositions are provided asready-to-use sterile emulsions.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated as immediate or modified release dosageforms, including delayed-, sustained, pulsed-, controlled, targeted-,and programmed-release forms.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated as a suspension, solid, semi-solid, orthixotropic liquid, for administration as an implanted depot. In oneembodiment, the pharmaceutical compositions provided herein aredispersed in a solid inner matrix, which is surrounded by an outerpolymeric membrane that is insoluble in body fluids but allows theactive ingredient in the pharmaceutical compositions diffuse through.

Suitable inner matrixes include, but are not limited to,polymethylmethacrylate, polybutyl-methacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers, such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinyl alcohol, andcross-linked partially hydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include but are not limited to,polyethylene, polypropylene, ethylene/propylene copolymers,ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers,silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinatedpolyethylene, polyvinylchloride, vinyl chloride copolymers with vinylacetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer.

C. Topical Administration

The pharmaceutical compositions provided herein can be administeredtopically to the skin, orifices, or mucosa. The topical administration,as used herein, includes (intra)dermal, conjunctival, intracorneal,intraocular, ophthalmic, auricular, transdermal, nasal, vaginal,urethral, respiratory, and rectal administration.

The pharmaceutical compositions provided herein can be formulated in anydosage forms that are suitable for topical administration for local orsystemic effect, including emulsions, solutions, suspensions, creams,gels, hydrogels, ointments, dusting powders, dressings, elixirs,lotions, suspensions, tinctures, pastes, foams, films, aerosols,irrigations, sprays, suppositories, bandages, and dermal patches. Thetopical formulation of the pharmaceutical compositions provided hereincan also comprise liposomes, micelles, microspheres, nanosystems, andmixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use inthe topical formulations provided herein include, but are not limitedto, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles,antimicrobial agents or preservatives against the growth ofmicroorganisms, stabilizers, solubility enhancers, isotonic agents,buffering agents, antioxidants, local anesthetics, suspending anddispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, penetration enhancers,cryoprotectants, lyoprotectants, thickening agents, and inert gases.

The pharmaceutical compositions can also be administered topically byelectroporation, iontophoresis, phonophoresis, sonophoresis, ormicroneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp.,Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc.,Tualatin, Oreg.).

The pharmaceutical compositions provided herein can be provided in theforms of ointments, creams, and gels. Suitable ointment vehicles includeoleaginous or hydrocarbon vehicles, including lard, benzoinated lard,olive oil, cottonseed oil, and other oils, white petrolatum;emulsifiable or absorption vehicles, such as hydrophilic petrolatum,hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles,such as hydrophilic ointment; water-soluble ointment vehicles, includingpolyethylene glycols of varying molecular weight; emulsion vehicles,either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions,including cetyl alcohol, glyceryl monostearate, lanolin, and stearicacid (see, Remington: The Science and Practice of Pharmacy, supra).These vehicles are emollient but generally require addition ofantioxidants and preservatives.

Suitable cream base can be oil-in-water or water-in-oil. Suitable creamvehicles may be water-washable, and contain an oil phase, an emulsifier,and an aqueous phase. The oil phase is also called the “internal” phase,which is generally comprised of petrolatum and a fatty alcohol such ascetyl or stearyl alcohol. The aqueous phase usually, although notnecessarily, exceeds the oil phase in volume, and generally contains ahumectant. The emulsifier in a cream formulation may be a nonionic,anionic, cationic, or amphoteric surfactant.

Gels are semisolid, suspension-type systems. Single-phase gels containorganic macromolecules distributed substantially uniformly throughoutthe liquid carrier. Suitable gelling agents include, but are not limitedto, crosslinked acrylic acid polymers, such as carbomers,carboxypolyalkylenes, and CARBOPOL®; hydrophilic polymers, such aspolyethylene oxides, polyoxyethylene-poly oxypropylene copolymers, andpolyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose; gums, such as tragacanthand xanthan gum; sodium alginate; and gelatin. In order to prepare auniform gel, dispersing agents such as alcohol or glycerin can be added,or the gelling agent can be dispersed by trituration, mechanical mixing,and/or stirring.

The pharmaceutical compositions provided herein can be administeredrectally, urethrally, vaginally, or perivaginally in the forms ofsuppositories, pessaries, bougies, poultices or cataplasm, pastes,powders, dressings, creams, plasters, contraceptives, ointments,solutions, emulsions, suspensions, tampons, gels, foams, sprays, orenemas. These dosage forms can be manufactured using conventionalprocesses as described in Remington: The Science and Practice ofPharmacy, supra.

Rectal, urethral, and vaginal suppositories are solid bodies forinsertion into body orifices, which are solid at ordinary temperaturesbut melt or soften at body temperature to release the activeingredient(s) inside the orifices. Pharmaceutically acceptable carriersutilized in rectal and vaginal suppositories include bases or vehicles,such as stiffening agents, which produce a melting point in theproximity of body temperature, when formulated with the pharmaceuticalcompositions provided herein; and antioxidants as described herein,including bisulfite and sodium metabisulfite. Suitable vehicles include,but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin,carbowax (polyoxyethyleneglycol), spermaceti, paraffin, white and yellowwax, and appropriate mixtures of mono-, di- and triglycerides of fattyacids, and hydrogels, such as polyvinyl alcohol, hydroxyethylmethacrylate, and poly acrylic acid. Combinations of the variousvehicles can also be used. Rectal and vaginal suppositories may beprepared by compressing or molding. The typical weight of a rectal andvaginal suppository is about 2 to about 3 g.

The pharmaceutical compositions provided herein can be administeredophthalmically in the forms of solutions, suspensions, ointments,emulsions, gel-forming solutions, powders for solutions, gels, ocularinserts, and implants.

The pharmaceutical compositions provided herein can be administeredintranasally or by inhalation to the respiratory tract. Thepharmaceutical compositions can be provided in the form of an aerosol orsolution for delivery using a pressurized container, pump, spray,atomizer, such as an atomizer using electrohydrodynamics to produce afine mist, or nebulizer, alone or in combination with a suitablepropellant, such as 1,1,1,2-tetrafluoroethane or1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions canalso be provided as a dry powder for insufflation, alone or incombination with an inert carrier such as lactose or phospholipids; andnasal drops. For intranasal use, the powder can comprise a bioadhesiveagent, including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump,spray, atomizer, or nebulizer can be formulated to contain ethanol,aqueous ethanol, or a suitable alternative agent for dispersing,solubilizing, or extending release of the active ingredient providedherein; a propellant as solvent; and/or a surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

The pharmaceutical compositions provided herein can be micronized to asize suitable for delivery by inhalation, such as about 50 micrometersor less, or about 10 micrometers or less. Particles of such sizes can beprepared using a comminuting method known to those skilled in the art,such as spiral jet milling, fluid bed jet milling, supercritical fluidprocessing to form nanoparticles, high pressure homogenization, or spraydrying.

Capsules, blisters, and cartridges for use in an inhaler or insufflatorcan be formulated to contain a powder mix of the pharmaceuticalcompositions provided herein; a suitable powder base, such as lactose orstarch; and a performance modifier, such as I-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate. Other suitable excipients or carriers include, but are notlimited to, dextran, glucose, maltose, sorbitol, xylitol, fructose,sucrose, and trehalose. The pharmaceutical compositions provided hereinfor inhaled/intranasal administration can further comprise a suitableflavor, such as menthol and levomenthol; and/or sweeteners, such assaccharin and saccharin sodium.

The pharmaceutical compositions provided herein for topicaladministration can be formulated to be immediate release or modifiedrelease, including delayed-, sustained-, pulsed-, controlled-, targeted,and programmed release.

D. Modified Release

The pharmaceutical compositions provided herein can be formulated as amodified release dosage form. As used herein, the term “modifiedrelease” refers to a dosage form in which the rate or place of releaseof the active ingredient(s) is different from the at of an immediatedosage form when administered by the same route. Modified release dosageforms include, but are not limited to, delayed-, extended-, prolonged-,sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-,programmed-release, and gastric retention dosage forms. Thepharmaceutical compositions in modified release dosage forms can beprepared using a variety of modified release devices and methods knownto those skilled in the art, including, but not limited to, matrixcontrolled release devices, osmotic controlled release devices,multiparticulate controlled release devices, ion-exchange resins,enteric coatings, multilayered coatings, microspheres, liposomes, andcombinations thereof. The release rate of the active ingredient(s) canalso be modified by varying the particle sizes and polymorphorism of theactive ingredient(s).

Examples of modified release include, but are not limited to, thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474;5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324;6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461;6,419,961; 6,589,548; 6,613,358; and 6,699,500.

1. Matrix Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated using a matrix controlled release deviceknown to those skilled in the art (see, Takada et al. in “Encyclopediaof Controlled Drug Delivery,” Vol. 2, Mathiowitz Ed., Wiley, 1999).

In certain embodiments, the pharmaceutical compositions provided hereinin a modified release dosage form is formulated using an erodible matrixdevice, which is water-swellable, erodible, or soluble polymers,including, but not limited to, synthetic polymers, and naturallyoccurring polymers and derivatives, such as polysaccharides andproteins.

Materials useful in forming an erodible matrix include, but are notlimited to, chitin, chitosan, dextran, and pullulan; gum agar, gumarabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gumghatti, guar gum, xanthan gum, and scleroglucan; starches, such asdextrin and maltodextrin; hydrophilic colloids, such as pectin;phosphatides, such as lecithin; alginates; propylene glycol alginate;gelatin; collagen; cellulosics, such as ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC);polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerolfatty acid esters; polyacrylamide; polyacrylic acid; copolymers ofethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc.,Piscataway, N.J.); poly(2-hydroxyethyl-methacrylate); polylactides;copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lacticacid-glycolic acid copolymers; poly-D-(−)-3-hydroxybutyric acid, andother acrylic acid derivatives, such as homopolymers and copolymers ofbutylmethacrylate, methyl methacrylate, ethyl methacrylate,ethylacrylate, (2-dimethylaminoethyl)methacrylate, and(trimethylaminoethyl)methacrylate chloride.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated with a non-erodible matrix device. The activeingredient(s) is dissolved or dispersed in an inert matrix and isreleased primarily by diffusion through the inert matrix onceadministered. Materials suitable for use as anon-erodible matrix deviceinclude, but are not limited to, insoluble plastics, such aspolyethylene, polypropylene, polyisoprene, polyisobutylene,polybutadiene, polymethylmethacrylate, polybutylmethacrylate,chlorinated polyethylene, polyvinylchloride, methyl acrylate-methylmethacrylate copolymers, ethylene-vinyl acetate copolymers,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethyleneand propylene, ionomer polyethylene terephthalate, butyl rubbers,epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer,ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticizednylon, plasticized polyethylene terephthalate, natural rubber, siliconerubbers, poly dimethylsiloxanes, and silicone carbonate copolymers;hydrophilic polymers, such as ethyl cellulose, cellulose acetate,crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate;and fatty compounds, such as carnauba wax, microcrystalline wax, andtriglycerides.

In a matrix controlled release system, the desired release kinetics canbe controlled, for example, via the polymer type employed, the polymerviscosity, the particle sizes of the polymer and/or the activeingredient(s), the ratio of the active ingredient(s) versus the polymer,and other excipients or carriers in the compositions.

The pharmaceutical compositions provided herein in a modified releasedosage form can be prepared by methods known to those skilled in theart, including direct compression, dry or wet granulation followed bycompression, and melt-granulation followed by compression.

2. Osmotic Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated using an osmotic controlled releasedevice, including, but not limited to, one-chamber system, two-chambersystem, asymmetric membrane technology (AMT), and extruding core system(ECS). In general, such devices have at least two components: (a) a corewhich contains an active ingredient; and (b) a semipermeable membranewith at least one delivery port, which encapsulates the core. Thesemipermeable membrane controls the influx of water to the core from anaqueous environment of use so as to cause drug release by extrusionthrough the delivery port(s).

In addition to the active ingredient(s), the core of the osmotic deviceoptionally includes an osmotic agent, which creates a driving force fortransport of water from the environment of use into the core of thedevice. One class of osmotic agents is water-swellable hydrophilicpolymers, which are also referred to as “osmopolymers” and “hydrogels.”Suitable water-swellable hydrophilic polymers as osmotic agents include,but are not limited to, hydrophilic vinyl and acrylic polymers,polysaccharides such as calcium alginate, polyethylene oxide (PEO),polyethylene glycol (PEG), polypropylene glycol (PPG),poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomerssuch as methyl methacrylate and vinyl acetate, hydrophilic polyurethanescontaining large PEO blocks, sodium croscarmellose, carrageenan,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) andcarboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin,xanthan gum, and sodium starch glycolate.

The other class of osmotic agents is osmogens, which are capable ofimbibing water to affect an osmotic pressure gradient across the barrierof the surrounding coating. Suitable osmogens include, but are notlimited to, inorganic salts, such as magnesium sulfate, magnesiumchloride, calcium chloride, sodium chloride, lithium chloride, potassiumsulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithiumsulfate, potassium chloride, and sodium sulfate; sugars, such asdextrose, fructose, glucose, inositol, lactose, maltose, mannitol,raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids,such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleicacid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamicacid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea;and mixtures thereof.

Osmotic agents of different dissolution rates can be employed toinfluence how rapidly the active ingredient(s) is initially deliveredfrom the dosage form. For example, amorphous sugars, such as MANNOGEM™EZ (SPI Pharma, Lewes, DE) can be used to provide faster delivery duringthe first couple of hours to promptly produce the desired therapeuticeffect, and gradually and continually release of the remaining amount tomaintain the desired level of therapeutic or prophylactic effect over anextended period of time. In this case, the active ingredient(s) isreleased at such a rate to replace the amount of the active ingredientmetabolized and excreted.

The core can also include a wide variety of other excipients andcarriers as described herein to enhance the performance of the dosageform or to promote stability or processing

Materials useful in forming the semipermeable membrane include variousgrades of acrylics, vinyls, ethers, polyamides, polyesters, andcellulosic derivatives that are water-permeable and water-insoluble atphysiologically relevant pHs, or are susceptible to being renderedwater-insoluble by chemical alteration, such as crosslinking. Examplesof suitable polymers useful in forming the coating, include plasticized,unplasticized, and reinforced cellulose acetate (CA), cellulosediacetate, cellulose triacetate, CA propionate, cellulose nitrate,cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CAdimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyloxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,poly(acrylic) acids and esters and poly-(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturalwaxes, and synthetic waxes.

Semipermeable membrane can also be a hydrophobic microporous membrane,wherein the pores are substantially filled with a gas and are not wettedby the aqueous medium but are permeable to water vapor, as disclosed inU.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeablemembrane are typically composed of hydrophobic polymers such aspolyalkenes, polyethylene, polypropylene, poly tetrafluoroethylene,polyacrylic acid derivatives, polyethers, polysulfones,polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidenefluoride, polyvinyl esters and ethers, natural waxes, and syntheticwaxes.

The delivery port(s) on the semipermeable membrane can be formedpost-coating by mechanical or laser drilling. Delivery port(s) can alsobe formed in situ by erosion of a plug of water-soluble material or byrupture of a thinner portion of the membrane over an indentation in thecore. In addition, delivery ports can be formed during coating process,as in the case of asymmetric membrane coatings of the type disclosed inU.S. Pat. Nos. 5,612,059 and 5,698,220.

The total amount of the active ingredient(s) released and the releaserate can substantially by modulated via the thickness and porosity ofthe semipermeable membrane, the composition of the core, and the number,size, and position of the delivery ports.

The pharmaceutical compositions in an osmotic controlled-release dosageform can further comprise additional conventional excipients or carriersas described herein to promote performance or processing of theformulation.

The osmotic controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art(see, Remington: The Science and Practice of Pharmacy, supra; Santus andBaker, J. Controlled Release 1995, 35, 1-21; Verma et al., DrugDevelopment and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J.Controlled Release 2002, 79, 7-27).

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as AMT controlled-release dosage form, which comprises anasymmetric osmotic membrane that coats a core comprising the activeingredient(s) and other pharmaceutically acceptable excipients orcarriers. See, U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMTcontrolled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art,including direct compression, dry granulation, wet granulation, and adip-coating method.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as ESC controlled-release dosage form, which comprises anosmotic membrane that coats a core comprising the active ingredient(s),a hydroxylethyl cellulose, and other pharmaceutically acceptableexcipients or carriers.

3. Multiparticulate Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated as a multiparticulate controlled releasedevice, which comprises a multiplicity of particles, granules, orpellets, ranging from about 10 μm to about 3 mm, about 50 μm to about2.5 mm, or from about 100 μm to about 1 mm in diameter. Suchmultiparticulates can be made by the processes known to those skilled inthe art, including wet-and dry-granulation, extrusion/spheronization,roller-compaction, melt-congealing, and by spray-coating seed cores.See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker:1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

Other excipients or carriers as described herein can be blended with thepharmaceutical compositions to aid in processing and forming themultiparticulates. The resulting particles can themselves constitute themultiparticulate device or can be coated by various film-formingmaterials, such as enteric polymers, water-swellable, and water-solublepolymers. The multiparticulates can be further processed as a capsule ora tablet.

4. Targeted Delivery

The pharmaceutical compositions provided herein can also be formulatedto be targeted to a particular tissue, receptor, or other area of thebody of the subject to be treated, including liposome-, resealederythrocyte-, and antibody-based delivery systems. Examples include, butare not limited to, those disclosed in U.S. Pat. Nos. 6,316,652;6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751;6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534; 5,985,307;5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874.

Methods of Use

In one embodiment, provided herein is a method for treating, preventing,or ameliorating one or more symptoms of a PI3K-mediated disorder,disease, or condition in a subject, comprising administering to thesubject a therapeutically effective amount of a compound disclosedherein, e.g., a compound of Formula I, or an enantiomer, a mixture ofenantiomers, a mixture of two or more diastereomers, or an isotopicvariant thereof; or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof.

In certain embodiments, the PI3K is a wild type PI3K. In certainembodiments, the PI3K is a PI3K variant.

In certain embodiments, the PI3K is a Class I kinase. In certainembodiments, the PI3K is PI3Kα, PI3Kβ, PI3Kδ, or PI3Kγ. In certainembodiments, the PI3K is p110α, p110β, p110δ, or p110γ. In certainembodiments, the PI3K is a wild type of a Class I kinase. In certainembodiments, the PI3K is a variant of a Class I kinase.

In certain embodiments, the PI3K is p110α. In certain embodiments, thePI3K is a wild type of p110α. In certain embodiments, the PI3K is ap110α mutant. In certain embodiments, the p110α mutant is R38H, G106V,K111N, K227E, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K,Q546P, E453Q, H710P, I800L, T1025S, M1043I, M1043V, H1047L, H1047R, orH1047Y. In certain embodiments, the p110α mutant is R38H, K111N, N345K,C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, I800L, T1025S,M1043I, H1047L, H1047R, or H1047Y. In certain embodiments, the p110αmutant is C420R, E542K, E545A, E545K, Q546K, I800L, M1043I, H1047L, orH1047Y.

In certain embodiments, the PI3K is PI3Kγ. In certain embodiments, thePI3K is a wild type of PI3Kγ. In certain embodiments, the PI3K is avariant of PI3Kγ.

In certain embodiments, the compound provided herein selectively targetsPI3Kδ. In certain embodiments, the compound provided herein selectivelytargets a wild type of PI3Kδ. In certain embodiments, the compoundprovided herein selectively targets a variant of PI3Kδ.

In certain embodiments, the compound provided herein is a selectiveinhibitor of PI3Kδ. In certain embodiments, the compound provided hereinhas a selectivity against PI3Kδ over PI3Kα ranging from about 2 fold,about 4 fold, about 8 fold, about 20 fold, about 50 fold, about 100fold, about 200 fold, about 500 fold, or about 1000 fold. In certainembodiments, the compound provided herein has a selectivity againstPI3Kδ over PI3Kβ ranging from about 2 fold, about 4 fold, about 8 fold,about 20 fold, about 50 fold, about 100 fold, about 200 fold, about 500fold, or about 1000 fold. In certain embodiments, the compound providedherein has a selectivity against PI3Kδ over PI3Kγ ranging from about 2fold, about 4 fold, about 8 fold, about 20 fold, about 50 fold, about100 fold, about 200 fold, about 500 fold, or about 1000 fold. In certainembodiments, the compound provided herein has a selectivity against PI3Kover mTOR ranging from about 2 fold, about 4 fold, about 8 fold, about20 fold, about 50 fold, about 100 fold, about 200 fold, about 500 fold,or about 1000 fold.

In certain embodiments, the compound provided herein is a selectiveinhibitor of PI3Kβ. In certain embodiments, the compound provided hereinhas a selectivity against PI3Kβ over PI3Kα ranging from about 2 fold,about 4 fold, about 8 fold, about 20 fold, about 50 fold, about 100fold, about 200 fold, about 500 fold, or about 1000 fold. In certainembodiments, the compound provided herein has a selectivity againstPI3Kβ over PI3Kδ ranging from about 2 fold, about 4 fold, about 8 fold,about 20 fold, about 50 fold, about 100 fold, about 200 fold, about 500fold, or about 1000 fold. In certain embodiments, the compound providedherein has a selectivity against PI3Kβ over PI3Kγ ranging from about 2fold, about 4 fold, about 8 fold, about 20 fold, about 50 fold, about100 fold, about 200 fold, about 500 fold, or about 1000 fold. In certainembodiments, the compound provided herein has a selectivity againstPI3Kβ over mTOR ranging from about 2 fold, about 4 fold, about 8 fold,about 20 fold, about 50 fold, about 100 fold, about 200 fold, about 500fold, or about 1000 fold.

In certain embodiments, the compound provided herein is a selectiveinhibitor of PI3Kδ and PI3K$. In certain embodiments, the compoundprovided herein has a selectivity against PI3Kδ and PI3Kβ over PI3Kαranging from about 2 fold, about 4 fold, about 8 fold, about 20 fold,about 50 fold, about 100 fold, about 200 fold, about 500 fold, or about1000 fold. In certain embodiments, the compound provided herein has aselectivity against PI3Kδ and PI3Kβ over PI3Kγ ranging from about 2fold, about 4 fold, about 8 fold, about 20 fold, about 50 fold, about100 fold, about 200 fold, about 500 fold, or about 1000 fold. In certainembodiments, the compound provided herein has a selectivity against PI3Kand PI3Kβ over mTOR ranging from about 2 fold, about 4 fold, about 8fold, about 20 fold, about 50 fold, about 100 fold, about 200 fold,about 500 fold, or about 1000 fold.

In certain embodiments, the PI3K is a Class IV kinase. In certainembodiments, the PI3K is a wild type of a Class IV kinase. In certainembodiments, the PI3K is a variant of a Class IV kinase. In certainembodiments, the PI3K is mTOR, ATM, ATR, or DNA-PK. In certainembodiments, the PI3K is mTOR.

In another embodiments, provided herein is a method for treating,preventing, or ameliorating one or more symptoms of a proliferativedisease in a subject, comprising administering to the subject atherapeutically effective amount of a compound disclosed herein, e.g., acompound of Formula I, or an enantiomer, a mixture of enantiomers, amixture of two or more diastereomers, or an isotopic variant thereof; ora pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof.

In certain embodiments, the subject is a mammal. In certain embodiments,the subject is a human. In certain embodiments, the subject is a primateother than a human, a farm animal such as cattle, a sport animal, or apet such as a horse, dog, or cat.

In certain embodiments, the proliferative disease is cancer. In certainembodiments, the proliferative disease is hematological cancer. Incertain embodiments, the proliferative disease is an inflammatorydisease. In certain embodiments, the proliferative disease is an immunedisorder.

The disorders, diseases, or conditions treatable with a compoundprovided herein, include, but are not limited to, (1) inflammatory orallergic diseases, including systemic anaphylaxis and hypersensitivitydisorders, atopic dermatitis, urticaria, drug allergies, insect stingallergies, food allergies (including celiac disease and the like), andmastocytosis; (2) inflammatory bowel diseases, including Crohn'sdisease, ulcerative colitis, ileitis, and enteritis; (3) vasculitis, andBehcet's syndrome; (4) psoriasis and inflammatory dermatoses, includingdermatitis, eczema, atopic dermatitis, allergic contact dermatitis,urticaria, viral cutaneous pathologies including those derived fromhuman papillomavirus, HIV or RLV infection, bacterial, flugal, and otherparasital cutaneous pathologies, and cutaneous lupus erythematosus; (5)asthma and respiratory allergic diseases, including allergic asthma,exercise induced asthma, allergic rhinitis, otitis media, allergicconjunctivitis, hypersensitivity lung diseases, and chronic obstructivepulmonary disease; (6) autoimmune diseases, including arthritis(including rheumatoid and psoriatic), systemic lupus erythematosus, typeI diabetes, myasthenia gravis, multiple sclerosis, Graves' disease, andglomerulonephritis; (7) graft rejection (including allograft rejectionand graft-v-host disease), e.g., skin graft rejection, solid organtransplant rejection, bone marrow transplant rejection; (8) fever; (9)cardiovascular disorders, including acute heart failure, hypotension,hypertension, angina pectoris, myocardial infarction, cardiomyopathy,congestive heart failure, atherosclerosis, coronary artery disease,restenosis, and vascular stenosis; (10) cerebrovascular disorders,including traumatic brain injury, stroke, ischemic reperfusion injuryand aneurysm; (11) cancers of the breast, skin, prostate, cervix,uterus, ovary, testes, bladder, lung, liver, larynx, oral cavity, colonand gastrointestinal tract (e.g., esophagus, stomach, pancreas), brain,thyroid, blood, and lymphatic system; (12) fibrosis, connective tissuedisease, and sarcoidosis, (13) genital and reproductive conditions,including erectile dysfunction; (14) gastrointestinal disorders,including gastritis, ulcers, nausea, pancreatitis, and vomiting;(15)neurologic disorders, including Alzheimer's disease; (16) sleepdisorders, including insomnia, narcolepsy, sleep apnea syndrome, andPickwick Syndrome; (17) pain; (18) renal disorders; (19) oculardisorders, including glaucoma; and (20) infectious diseases, includingHIV.

In certain embodiments, the cancer treatable with the methods providedherein includes, but is not limited to, (1) leukemias, including, butnot limited to, acute leukemia, acute lymphocytic leukemia, acutemyelocytic leukemias such as myeloblastic, promyelocytic,myelomonocytic, monocytic, erythroleukemia leukemias and myelodysplasticsyndrome or a symptom thereof (such as anemia, thrombocytopenia,neutropenia, bicytopenia or pancytopenia), refractory anemia (RA), RAwith ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB intransformation (RAEB-T), preleukemia, and chronic myelomonocyticleukemia (CMML), (2) chronic leukemias, including, but not limited to,chronic myelocytic (granulocytic) leukemia, chronic lymphocyticleukemia, and hairy cell leukemia; (3) polycythemia vera; (4)lymphomas,including, but not limited to, Hodgkin's disease and non-Hodgkin'sdisease; (5) multiple myelomas, including, but not limited to,smoldering multiple myeloma, nonsecretory myeloma, osteoscleroticmyeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullaryplasmacytoma; (6) Waldenström's macroglobulinemia; (7) monoclonalgammopathy of undetermined significance; (8) benign monoclonalgammopathy; (9) heavy chain disease; (10) bone and connective tissuesarcomas, including, but not limited to, bone sarcoma, osteosarcoma,chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor,fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissuesarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi'ssarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastaticcancers, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; (11)brain tumors, including, but not limited to, glioma, astrocytoma, brainstem glioma, ependymoma, oligodendroglioma, nonglial tumor, acousticneurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma,pineoblastoma, and primary brain lymphoma; (12) breast cancer,including, but not limited to, adenocarcinoma, lobular (small cell)carcinoma, intraductal carcinoma, medullary breast cancer, mucinousbreast cancer, tubular breast cancer, papillary breast cancer, primarycancers, Paget's disease, and inflammatory breast cancer; (13) adrenalcancer, including, but not limited to, pheochromocytom andadrenocortical carcinoma; (14)thyroid cancer, including, but not limitedto, papillary or follicular thyroid cancer, medullary thyroid cancer,and anaplastic thyroid cancer; (15) pancreatic cancer, including, butnot limited to, insulinoma, gastrinoma, glucagonoma, vipoma,somatostatin-secreting tumor, and carcinoid or islet cell tumor; (16)pituitary cancer, including, but limited to, Cushing's disease,prolactin-secreting tumor, acromegaly, and diabetes insipius; (17) eyecancer, including, but not limited, to ocular melanoma such as irismelanoma, choroidal melanoma, and cilliary body melanoma, andretinoblastoma; (18)vaginal cancer, including, but not limited to,squamous cell carcinoma, adenocarcinoma, and melanoma; (19) vulvarcancer, including, but not limited to, squamous cell carcinoma,melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget'sdisease; (20) cervical cancers, including, but not limited to, squamouscell carcinoma, and adenocarcinoma; (21) uterine cancer, including, butnot limited to, endometrial carcinoma and uterine sarcoma; (22) ovariancancer, including, but not limited to, ovarian epithelial carcinoma,borderline tumor, germ cell tumor, and stromal tumor; (23) esophagealcancer, including, but not limited to, squamous cancer, adenocarcinoma,adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamouscarcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oatcell (small cell) carcinoma; (24) stomach cancer, including, but notlimited to, adenocarcinoma, fungating (polypoid), ulcerating,superficial spreading, diffusely spreading, malignant lymphoma,liposarcoma, fibrosarcoma, and carcinosarcoma; (25) colon cancer; (26)rectal cancer; (27) liver cancer, including, but not limited to,hepatocellular carcinoma and hepatoblastoma; (28) gallbladder cancer,including, but not limited to, adenocarcinoma; (29) cholangiocarcinomas,including, but not limited to, pappillary, nodular, and diffuse; (30)lung cancer, including, but not limited to, non-small cell lung cancer,squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma,large-cell carcinoma, and small-cell lung cancer; (31) testicularcancer, including, but not limited to, germinal tumor, seminoma,anaplastic, classic (typical), spermatocytic, nonseminoma, embryonalcarcinoma, teratoma carcinoma, and choriocarcinoma (yolk-sac tumor);(32) prostate cancer, including, but not limited to, adenocarcinoma,leiomyosarcoma, and rhabdomyosarcoma; (33) penal cancer; (34) oralcancer, including, but not limited to, squamous cell carcinoma; (35)basal cancer; (36) salivary gland cancer, including, but not limited to,adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma;(37) pharynx cancer, including, but not limited to, squamous cell cancerand verrucous; (38) skin cancer, including, but not limited to, basalcell carcinoma, squamous cell carcinoma and melanoma, superficialspreading melanoma, nodular melanoma, lentigo malignant melanoma, andacral lentiginous melanoma: (39) kidney cancer, including, but notlimited to, renal cell cancer, adenocarcinoma, hypernephroma,fibrosarcoma, and transitional cell cancer (renal pelvis and/or uterer);(40) Wilms' tumor: (41) bladder cancer, including, but not limited to,transitional cell carcinoma, squamous cell cancer, adenocarcinoma, andcarcinosarcoma; and other cancer, including, not limited to,myxosarcoma, osteogenic sarcoma, endotheliosarcoma,lymphangio-endotheliosarcoma, mesothelioma, synovioma, hemangioblastoma,epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweatgland carcinoma, sebaceous gland carcinoma, papillary carcinoma, andpapillary adenocarcinomas (See Fishman et al., 1985, Medicine, 2d Ed.,J.B. Lippincott Co., Philadelphia and Murphy et al., 1997, InformedDecisions: The Complete Book of Cancer Diagnosis, Treatment, andRecovery, Viking Penguin, Penguin Books U.S. A., Inc., United States ofAmerica).

Depending on the disorder, disease, or condition to be treated, and thesubject's condition, the compounds or pharmaceutical compositionsprovided herein can be administered by oral, parenteral (e.g.,intramuscular, intraperitoneal, intravenous, ICV, intracistemalinjection or infusion, subcutaneous injection, or implant), inhalation,nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal orlocal) routes of administration and can be formulated, alone ortogether, in suitable dosage unit with pharmaceutically acceptableexcipients, carriers, adjuvants, and vehicles appropriate for each routeof administration. Also provided is administration of the compounds orpharmaceutical compositions provided herein in a depot formulation, inwhich the active ingredient is released over a predefined time period.

In the treatment, prevention, or amelioration of one or more symptoms ofthe disorders, diseases, or conditions described herein, an appropriatedosage level generally is ranging from about 0.001 to 100 mg per kgsubject body weight per day (mg/kg per day), from about 0.01 to about 75mg/kg per day, from about 0.1 to about 50 mg/kg per day, from about 0.5to about 25 mg/kg per day, or from about 1 to about 20 mg/kg per day,which can be administered in single or multiple doses. Within thisrange, the dosage can be ranging from about 0.005 to about 0.05, fromabout 0.05 to about 0.5, from about 0.5 to about 5.0, from about 1 toabout 15, from about 1 to about 20, or from about 1 to about 50 mg/kgper day.

For oral administration, the pharmaceutical compositions provided hereincan be formulated in the form of tablets containing from about 1.0 toabout 1,000 mg of the active ingredient, in one embodiment, about 1,about 5, about 10, about 15, about 20, about 25, about 50, about 75,about 100, about 150, about 200, about 250, about 300, about 400, about500, about 600, about 750, about 800, about 900, and about 1,000 mg ofthe active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated. The pharmaceutical compositions can beadministered on a regimen of 1 to 4 times per day, including once,twice, three times, and four times per day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient can be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Also provided herein are methods of modulating PI3K activity, comprisingcontacting a PIK3 enzyme with a compound provided herein, e.g., acompound of Formula I, or an enantiomer, a mixture of enantiomers, amixture of two or more diastereomers, or an isotopic variant thereof; ora pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof. In one embodiment, the PIK3 enzyme is inside a cell.

In certain embodiments, the PI3K is a wild type PI3K. In certainembodiments, the PI3K is a PI3K variant.

In certain embodiments, the PI3K is a Class I kinase. In certainembodiments, the PI3K is PI3Kα, PI3Kβ, PI3Kδ, or PI3Kγ. In certainembodiments, the PI3K is p110α, p110β, p110δ, or p110γ. In certainembodiments, the PI3K is a wild type of a Class I kinase. In certainembodiments, the PI3K is a variant of a Class I kinase.

In certain embodiments, the PI3K is p110α. In certain embodiments, thePI3K is a wild type of p110α. In certain embodiments, the PI3K is ap110α mutant. In certain embodiments, the p110a mutant is R38H, G106V,K111N, K227E, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K,Q546P, E453Q, H710P, I800L, T1025S, M1043I, M1043V, H1047L, H1047R, orH1047Y. In certain embodiments, the p110α mutant is R38H, K111N, N345K,C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, I800L, T1025S,M1043I, H1047L, H1047R, or H1047Y. In certain embodiments, the p110αmutant is C420R, E542K, E545A, E545K, Q546K, I800L, M1043I, H1047L, orH1047Y.

In certain embodiments, the PI3K is PI3Kγ. In certain embodiments, thePI3K is a wild type of PI3Kγ. In certain embodiments, the PI3K is avariant of PI3Kγ.

In certain embodiments, the compound provided herein selectively targetsPI3Kγ. In certain embodiments, the compound provided herein selectivelytargets a wild type of PI3Kγ. In certain embodiments, the compoundprovided herein selectively targets a variant of PI3Kγ.

In certain embodiments, the PI3K is a Class IV kinase. In certainembodiments, the PI3K is a wild type of a Class IV kinase. In certainembodiments, the PI3K is a variant of a Class IV kinase. In certainembodiments, the PI3K is mTOR, ATM, ATR, or DNA-PK. In certainembodiments, the PI3K is mTOR.

In certain embodiments, the compound provided herein, e.g., a compoundof Formula I, or an enantiomer, a mixture of enantiomers, a mixture oftwo or more diastereomers, or an isotopic variant thereof, or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;shows inhibitory activity against a PI3K and a variant thereof.

In certain embodiments, the compound provided herein, e.g., a compoundof Formula I, or an enantiomer, a mixture of enantiomers, a mixture oftwo or more diastereomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;shows inhibitory activity against a wild type of a PI3K. In certainembodiments, the PI3K is PI3Kγ.

In certain embodiments, the compound provided herein, e.g., a compoundof Formula I, or an enantiomer, a mixture of enantiomers, a mixture oftwo or more diastereomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;shows inhibitory activity against a PI3K variant. In certainembodiments, the PI3K variant is a p110α mutant. In certain embodiments,the p110α mutant is C420R, E542K, E545A, E545K, Q546K, I800L, M1043I,H1047L, or H1047Y.

The compound provided herein, e.g., a compound of Formula I, or anenantiomer, a mixture of enantiomets, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; can also becombined or used in combination with other agents or therapies useful inthe treatment, prevention, or amelioration of one or more symptoms ofthe disorders, diseases, or conditions for which the compounds providedherein are useful, including asthma, allergic rhinitis, eczema,psoriasis, atopic dermatitis, fever, sepsis, systemic lupuserythematosus, diabetes, rheumatoid arthritis, multiple sclerosis,atherosclerosis, transplant rejection, inflammatory bowel disease,cancer, infectious diseases, and those pathologies noted herein.

Suitable other therapeutic agents can also include, but are not limitedto, (1) alpha-adrenergic agents; (2) antiarrhythmic agents; (3)anti-atherosclerotic agents, such as ACAT inhibitors; (4) antibiotics,such as anthracyclines, bleomycins, mitomycin, dactinomycin, andplicamycin; (5) anticancer agents and cytotoxic agents, e.g., alkylatingagents, such as nitrogen mustands, alkyl sulfonates, nitrosoureas,ethylenimines, and triazenes; (6) anticoagulants, such as acenocoumarol,argatroban, bivalirudin, lepirudin, fondaparinux, heparin, phenindione,warfarin, and ximelagatran; (7) anti-diabetic agents, such as biguanides(e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulins,meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride,glyburide, and glipizide), thiozolidinediones (e.g., troglitazone,rosiglitazone, and pioglitazone), and PPAR-gamma agonists; (8)antifungal agents, such as amorolfine, amphotericin B, anidulafungin,bifonazole, butenafine, butoconazole, caspofungin, ciclopirox,clotrimazole, econazole, fenticonazole, filipin, fluconazole,isoconazole, itraconazole, ketoconazole, micafungin, miconazole,naftifine, natamycin, nystatin, oxyconazole, ravuconazole, posaconazole,rimocidin, sertaconazole, sulconazole, terbinafine, terconazole,tioconazole, and voriconazole; (9) antiinflammatories, e.g.,non-steroidal anti-inflammatory agents, such as aceclofenac, acemetacin,amoxiprin, aspirin, azapropazone, benorilate, bromfenac, carprofen,celecoxib, choline magnesium salicylate, diclofenac, diflunisal,etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen,ibuprofen, indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen,lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, metamizole,methyl salicylate, magnesium salicylate, nabumetone, naproxen,nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam,salicyl salicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam,tiaprofenic acid, and tolmetin; (10) antimetabolites, such as folateantagonists, purine analogues, and pyrimidine analogues; (11)anti-platelet agents, such as GPIIb/IIIa blockers (e.g., abciximab,eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel,ticlopidine and CS-747), cilostazol, dipyridamole, and aspirin (12)antiproliferatives, such as methotrexate, FK506 (tacrolimus), andmycophenolate mofetil; (13) anti-TNF antibodies or soluble TNF receptor,such as etanercept, rapamycin, and leflunimide; (14) aP2 inhibitors;(15) beta-adrenergic agents, such as carvedilol and metoprolol; (16)bile acid sequestrants, such as questran; (17) calcium channel blockers,such as amlodipine besylate; (18) chemotherapeutic agents; (19)cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib;(20) cyclosporins; (21) cytotoxic drugs, such as azathioprine andcyclophosphamide; (22) diuretics, such as chlorothiazide,hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzothiazide, ethacrynic acid, ticrynafen,chlorthalidone, furosenide, muzolimine, bumetanide, triamterene,amiloride, and spironolactone; (23) endothelin converting enzyme (ECE)inhibitors, such as phosphoramidon; (24) enzymes, such asL-asparaginase; (25) Factor VIIa Inhibitors and Factor Xa Inhibitors;(26) farnesyl-protein transferase inhibitors; (27) fibrates; (28) growthfactor inhibitors, such as modulators of PDGF activity; (29) growthhormone secretagogues; (30) HMG CoA reductase inhibitors, such aspravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a.itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known asrosuvastatin, atavastatin, or visastatin); neutral endopeptidase (NEP)inhibitors; (31)hormonal agents, such as glucocorticoids (e.g.,cortisone), estrogens/antiestrogens, androgens/antiandrogens,progestins, and luteinizing hormone-releasing hormone antagonists, andoctreotide acetate; (32) immunosuppressants; (33) mineralocorticoidreceptor antagonists, such as spironolactone and eplerenone; (34)microtubule-disruptor agents, such as ecteinascidins; (35)microtubule-stabilizing agents, such as pacitaxel, docetaxel, andepothilones A-F; (36) MTP Inhibitors; (37)niacin; (38) phosphodiesteraseinhibitors, such as PDE III inhibitors (e.g., cilostazol) and PDE Vinhibitors (e.g., sildenafil, tadalafil, and vardenafil); (39)plant-derived products, such as vinca alkaloids, epipodophyllotoxins,and taxanes; (40) platelet activating factor (PAF) antagonists; (41)platinum coordination complexes, such as cisplatin, satraplatin, andcarboplatin; (42) potassium channel openers; (43) prenyl-proteintransferase inhibitors; (44) protein tyrosine kinase inhibitors; (45)renin inhibitors; (46) squalene synthetase inhibitors; (47) steroids,such as aldosterone, beclometasone, betamethasone, deoxycorticosteroneacetate, fludrocortisone, hydrocortisone (cortisol), prednisolone,prednisone, methylprednisolone, dexamethasone, and triamcinolone; (48)TNF-alpha inhibitors, such as tenidap; (49) thrombin inhibitors, such ashirudin; (50) thrombolytic agents, such as anistreplase, reteplase,tenecteplase, tissue plasminogen activator (WA), recombinant tPA,streptokinase, urokinase, prourokinase, and anisoylated plasminogenstreptokinase activator complex (APSAC); (51) thromboxane receptorantagonists, such as ifetroban; (52) topoisomerase inhibitors; (53)vasopeptidase inhibitors (dual NEP-ACE inhibitors), such as omapatrilatand gemopatrilat; and (54) other miscellaneous agents, such as,hydroxyurea, procarbazine, mitotane, hexamethylmelamine, and goldcompounds.

In certain embodiments, the other therapies that may be used incombination with the compounds provided herein include, but are notlimited to, surgery, endocrine therapy, biologic response modifiers(e.g., interferons, interleukins, and tumor necrosis factor (TNF)),hyperthermia and cryotherapy, and agents to attenuate any adverseeffects (e.g., antiemetics).

In certain embodiments, the other therapeutic agents that may be used incombination with the compounds provided herein include, but are notlimited to, alkylating drugs (mechlorethamine, chlorambucil,cyclophosphamide, melphalan, and ifosfamide), antimetabolites(cytarabine (also known as cytosine arabinoside or Ara-C), HDAC (highdose cytarabine), and methotrexate), purine antagonists and pyrimidineantagonists (6-mercaptopurine, 5-fluorouracil, cytarbine, andgemcitabine), spindle poisons (vinblastine, vincristine, andvinorelbine), podophyllotoxins (etoposide, irinotecan, and topotecan),antibiotics (daunorubicin, doxorubicin, bleomycin, and mitomycin),nitrosoureas (carmustine and lomustine), enzymes (asparaginase), andhormones (tamoxifen, leuprolide, flutamide, and megestrol), imatinib,adriamycin, dexamethasone, and cyclophosphamide. For a morecomprehensive discussion of updated cancer therapies; See,http://www.nci.nih.gov/, a list of the FDA approved oncology drugs athttp://www.fda.gov/cder/cancer/druglistframe.htm, and The Merck Manual,Seventeenth Ed. 1999, the entire contents of which are herebyincorporated by reference.

In another embodiment, the method provided herein comprisesadministration of a compound provided herein, e.g., a compound ofFormula I, or an enantiomer, a mixture of enantiomers, a mixture of twoor more diastereomers, or an isotopic variant thereof, or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof,together with administering one or more chemotherapeutic agents and/ortherapies selected from: alkylation agents (e.g., cisplatin,carboplatin); antimetabolites (e.g., methotrexate and 5-FU); antitumourantibiotics (e.g., adriamymycin and bleomycin); antitumour vegetablealkaloids (e.g., taxol and etoposide); antitumor hormones (e.g.,dexamethasone and tamoxifen); antitumour immunological agents (e.g.,interferon α, β, and γ); radiation therapy; and surgery. In certainembodiments, the one or more chemotherapeutic agents and/or therapiesare administered to the subject before, during, or after theadministration of the compound provided herein.

Such other agents, or drugs, can be administered, by a route and in anamount commonly used therefor, simultaneously or sequentially with thecompound provided herein, e.g., a compound of Formula I, or anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof. When a compoundprovided herein is used contemporaneously with one or more other drugs,a pharmaceutical composition containing such other drugs in addition tothe compound provided herein can be utilized, but is not required.Accordingly, the pharmaceutical compositions provided herein includethose that also contain one or more other active ingredients ortherapeutic agents, in addition to a compound provided herein.

The weight ratio of a compound provided herein to the second activeingredient can be varied, and will depend upon the effective dose ofeach ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound provided herein is combined with aNSAID, the weight ratio of the compound to the NSAID can range fromabout 1,000:1 to about 1:1,000, or about 200:1 to about 1:200.Combinations of a compound provided herein and other active ingredientswill generally also be within the aforementioned range, but in eachcase, an effective dose of each active ingredient should be used.

The compounds provided herein can also be provided as an article ofmanufacture using packaging materials well known to those of skill inthe art. See, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558; and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, and any packaging material suitable for a selectedformulation and intended mode of administration and treatment.

Provided herein also are kits which, when used by the medicalpractitioner, can simplify the administration of appropriate amounts ofactive ingredients to a subject. In certain embodiments, the kitprovided herein includes a container and a dosage form of a compoundprovided herein, e.g., a compound of Formula I, or an enantiomer, amixture of enantiomers, a mixture of two or more diastereomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In certain embodiments, the kit includes a container comprising a dosageform of the compound provided herein, e.g., a compound of Formula I, oran enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; in a containercomprising one or more other therapeutic agent(s) described herein.

Kits provided herein can further include devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, needle-less injectors drip bags, patches,and inhalers. The kits provided herein can also include condoms foradministration of the active ingredients.

Kits provided herein can further include pharmaceutically acceptablevehicles that can be used to administer one or more active ingredients.For example, if an active ingredient is provided in a solid form thatmust be reconstituted for parenteral administration, the kit cancomprise a sealed container of a suitable vehicle in which the activeingredient can be dissolved to form a particulate-free sterile solutionthat is suitable for parenteral administration. Examples ofpharmaceutically acceptable vehicles include, but are not limited to:aqueous vehicles, including, but not limited to, Water for InjectionUSP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection,Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection;water-miscible vehicles, including, but not limited to, ethyl alcohol,polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles,including, but not limited to, corn oil, cottonseed oil, peanut oil,sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

The disclosure will be further understood by the following non-limitingexamples.

EXAMPLES

As used herein, the symbols and conventions used in these processes,schemes and examples, regardless of whether a particular abbreviation isspecifically defined, are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Specifically, butwithout limitation, the following abbreviations may be used in theexamples and throughout the specification: g (grams); mg (milligrams),mL (milliliters); μL (microliters); M (molar); mM (millimolar); μM(micromolar); eq. (equivalent); mmol (millimoles); Hz (Hertz); MHz(megahertz); hr or hrs (hour or hours); min (minutes); and MS (massspectrometry).

For all of the following examples, standard work-up and purificationmethods known to those skilled in the art can be utilized. Unlessotherwise indicated, all temperatures are expressed in ° C. (degreesCentigrade). All reactions conducted at room temperature unlessotherwise noted. Synthetic methodologies illustrated herein are intendedto exemplify the applicable chemistry through the use of specificexamples and are not indicative of the scope of the disclosure.

Example 1 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-N-(1-phenylethyl)-1,3,5-triazin-2-amineA1

Compound A1 was prepared according to Scheme 1, where compound1(1-[4-chloro-6-(4-morpholinyl)-1,3,5-tianzin-2-yl]-2-(difluoromethyl)-1H-benzimidazole)was synthesized according to the procedure as described in U.S. Pat.Appl. Publ. No. 2007/244110, the disclosure of which is incorporatedherein by reference in its entirety.

A mixture of compound 1 (184 mg, 0.502 mmol) and α-methylbenzylamine(121 mg, 1.00 mmol) in dioxane (25 mL) was refluxed overnight. Themixture was poured into water to precipitate a white solid, which wasrecrystallized from ethanol to give 185 mg (81% yield) of compound A1 asa white solid: 97.1% purity (HPLC); MS m/z 452.2 (M+1); ¹H NMR (CDCl₃,500 MHz)(rotamers) δ 8.42 (d, J=8.0 Hz, 0.5H), 8.09 (d, J=8.0 Hz, 0.5H),7.90-7.86 (m, 1H), 7.65 (t, J_(HF)=53.5 Hz, 0.5H), 7.44-7.28 (m, 8H),5.59 (d, J=6.5 Hz, 0.5H), 5.19-5.06 (m, 1H), 3.76-3.91 (m, 8H), 1.63 (d,J=7.0 Hz, 3H) ppm.

Example 2 Synthesis of(S)-4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-N-(1-phenylethyl)-1,3,5-triazin-2-amineA2

Compound A2 was synthesized according to the procedure for compound A1,substituting (S)-α-methylbenzylamine in place of α-methylbenzylamine togive the product in 82% yield: 90.6% purity (HPLC); MS m/z 452.2 (M+1);¹H NMR (CDCl₃, 500 MHz) (rotamers) δ 8.42 (d, J=8.0 Hz, 0.5H), 8.09 (d,J=7.5 Hz, 0.5H), 7.91-7.85 (m, 1H), 7.65 (t, J_(HF)=54.0 Hz, 0.5H),7.41-7.22 (m, 8H), 5.61-5.57 (m, 0.5H), 5.25-5.17 ((m, 1H), 3.87-3.66(m, 8H), 1.68-1.61 (m, 3H)) ppm.

Example 3 Synthesis of(R)-4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-N-(1-phenylethyl)-1,3,5-triazin-2-amineA3

Compound A3 was synthesized according to the procedure for compound A1,substituting (R)-α-methylbenzylamine in place of α-methylbenzylamine togive a 68% yield of the product: 98.7% purity (HPLC); MS m/z 452 (M+1);¹H NMR (CDCl₃, 500 MHz) δ 8.41 (d, J=8.0 Hz, 0.5H), 8.08 (d, J=8.0 Hz,0.5H), 7.86 (m, 1H), 7.64 (t, J_(HF)=54.0 Hz, 0.5H), 7.44-7.19 (m,7.5H), 5.58 (d, J=7.5 Hz, 0.5H), 5.20 (m, 1H), 3.88-3.65 (m, 8H), 1.62(d, J=7.0 Hz, 3H) ppm.

Example 4 Synthesis of(S)-4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-N-(1-phenylpropyl)-1,3,5-triazin-2-amineA5

Compound A5 was synthesized according to the procedure for compound A1,substituting (S)-α-ethylbenzylamine in place of α-methylbenzylamine togive the product in 73% yield: 96.7% purity (LCMS); MS m/z: 466.2 (M+1);¹H NMR (DMSO₆, 500 MHz) δ (rotamers) δ 8.58 (d, J=8.5 Hz, 0.6H), 8.49(d, J=8.0 Hz, 0.6H), 8.46 (d, J=8.5 Hz, 0.4H), 8.11 (m, 0.4H), 7.91 (t,J_(HF)=53.0 Hz, 0.6H), 7.85-7.78 (m, 1H), 7.61 (t, J_(HF)=53.0 Hz,0.4H), 7.49 (t, J=7.5 Hz, 0.5H), 7.45-7.38 (m, 3H), 7.38-7.31 (m, 2H),7.27-7.20 (m, 1H), 4.90 (m, 1H), 3.88-3.55 (m, 8H), 1.95-1.65 (m, 1H),0.93 (m, 3H) ppm.

Example 5 Synthesis of(R)-4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-N-(1-phenylpropyl)-1,3,5-triazin-2-amineA6

Compound A6 was synthesized according to the procedure for compound A1,substituting (R)-α-ethylbenzylamine in place of α-methylbenzylamine togive a 62% yield of product: 96.2% purity (HPLC); MS m/z: 466.2 (M+1);¹H NMR (CDCl₃, 500 MHz) (rotamers) δ 8.41 (d, J=8.0 Hz, 0.4H), 8.11 (d,J=8.0 Hz, 0.6H), 7.89 (d, J=8.0 Hz, 0.4H), 7.86 (d, J=7.5 Hz, 0.6H),7.65 (t, J_(HF)=53.5 Hz, 0.6H), 7.46-7.25 (m, 7.4H), 5.62 (m, 0.5H),4.99 (m, 0.5H), 4.92 (m, 0.5H), 3.87-3.65 (m, 8H), 2.02-1.89 (m, 2H),1.04-0.98 (m, 3H) ppm.

Example 6 Synthesis of (R)-methyl2-((4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)amino)-2-phenylacetateA11

Saturated aqueous sodium bicarbonate was added dropwise to a solution of(R)-2-phenylglycine methyl ester hydrochloride (83 mg, 0.41 mmol) inwater (4 mL) at 0° C. until pH=8. Then the mixture was extracted withethyl acetate, dried over anhydrous sodium sulfate, and concentrated invacuo. The residue was added to a mixture of compound 1 (50 mg, 0.14mmol) in dioxane (5 mL) and the resulting mixture was refluxed for 4hrs. After the volatiles were removed in vacuo, the residue was taken upin water and ethyl acetate. The organic extracts were dried overanhydrous sodium sulfate and concentrated in vacuo. The crude productwas purified by silica gel column chromatography (ethylacetate/petroleum ether=1/5) to give 44 mg (65% yield) of compound A11as a yellow solid: 98.71% purity (LCMS); MS m/z: 496.1 (M+1); ¹H NMR(CDCl₃, 500 MHz) (rotamers) a 8.43 (d, J=8.0 Hz, 0.5H), 8.11 (d, J=8.0Hz, 0.5H), 7.88 (m, 1H), 7.64 (t, J_(HF)=53.5 Hz, 0.5H), 7.52-7.35 (m,7.5H), 6.33 and 6.25 (2d, J=6.5 and 6.0 Hz, 1H), 5.69 and 5.60 (2d,J=6.5 and 6.0 Hz, 1H), 3.89-3.70 (m, 11H) ppm.

Example 7 Synthesis of (S)-methyl2-((4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)amino)-2-phenylacetateA12

Compound A12 was synthesized according to the procedure for compoundA11, substituting (S)-2-phenylglycine methyl ester hydrochloride inplace of (R)-2-phenylglycine methyl ester hydrochloride to give theproduct in 67% yield: 95.5% purity (HPLC); MS m/z: 496.1 (M+1); ¹H NMR(CDCl₃, 500 MHz) δ 8.45 (d, J=8.5 Hz, 0.5H), 8.13 (d, J=8.0 Hz, 0.5H),7.89 (m, 1H), 7.64 (t, J_(HF)=53.5 Hz, 0.5H), 7.52-7.36 (m, 7.5H), 6.32and 6.25 (2d, J=6.0 and 5.5 Hz, 1H), 5.69 and 5.60 (2d, J=6.5 and 6.0Hz, 1H), 3.89-3.62 (m, 11H) ppm.

Example 8 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-N-(2-phenylpropan-2-yl)-1,3,5-triazin-2-amineA7

A mixture of compound 1 (184 mg, 0.502 mmol) and 2-phenylpropan-2-amine(170 mg, 1.26 mmol) in dioxane (5 mL) was refluxed overnight. Thevolatiles were removed in vacuo and the residue was separated by ethylacetate and water. The organic extracts were washed sequentially withaq. sodium hydroxide (1 N), water and brine, dried over anhydrous sodiumsulfate, and concentrated in vacuo. The crude product was purified byflash chromatography (10-21% ethyl acetate in petroleum ether) to give148 mg (63% yield) as a white solid. 99.6% purity (HPLC); MS m/z: 466.2(M+1); ¹H NMR (CDCl₃, 500 MHz) (rotamers) δ 8.45 (d, J=8.0 Hz, 0.5H),7.90 (d, J=7.5 Hz, 0.5H), 7.79 (d, J=8.0 Hz, 0.5H), 7.66 (t, J_(HF)=53.5Hz, 0.5H), 7.50 (d, J=8.0 Hz, 1H), 7.47-7.38 (m, 3.5H), 7.35-7.26 (m,2H), 7.22 (t, J=7.5 Hz, 0.5H), 7.13 (t, J=7.5 Hz, 0.5H), 6.82 (t,J_(HF)=53.5 Hz, 0.5H), 5.82 (s, 1H), 3.87 (m, 2H), 3.81 (m, 2H), 3.74(m, 1H), 3.67 (m, 1H), 3.41 (m, 1H), 3.31 (m, 1H), 1.80 and 1.78 (2s,6H) ppm.

Example 9 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-N-(2-(naphthalen-2-yl)propan-2-yl)-1,3,5-triazin-2-amineA13

Methylmagnesium bromide (3.6 mL, 3.0 Min tetrahydrofuran, 10.5 mmol) wasadded to a solution of naphthalene-2-carbonitrile (459 mg, 3.0 mmol) inanhydrous tetrahydrofuran (4 mL) at room temperature under a nitrogenatmosphere. The reaction mixture was heated in a microwave at 100° C.for 10 min. The resulting mixture was added titanium tetraisopropanolate(0.9 mL, 3.0 mmol) and then irradiated with microwave at 50° C. for 1hr. The mixture was poured into water and extracted withdichloromethane. The combined organic extracts were dried over anhydroussodium sulfate and concentrated in vacuo to give a crude product, whichwas triturated by the dropwise addition of hydrochloric acid in ether (1N) to precipitate 2-(naphthalen-2-yl)propan-2-amine as its hydrochloricacid salt (600 mg, 90%) as a yellow solid: 84.7% purity (LCMS); MS m/z:171 (M+1). The crude 2-(naphthalen-2-yl)propan-2-amine hydrochloride(246 mg, 1.09 mmol), compound 1 (200 mg, 0.550 mmol), and potassiumcarbonate (377 mg, 2.73 mmol) were suspended in dioxane (25 mL) and themixture was refluxed overnight. The mixture was diluted with water andextracted with ethyl acetate. The organic extracts were dried withanhydrous sodium sulfate and concentrated in vacuo. The crude productwas purified by preparative-HPLC to give 150 mg (53% yield) of compoundA13 as a white solid: 98.5% purity (HPLC); MS m/z: 516.2 (M+1); ¹H NMR(CDCl₃, 500 MHz) δ 8.43 (d, J=8.0 Hz, 0.6H), 7.98-7.36 (m, 10H),7.15-6.87 ((m, 1H), 6.26 (t, J=8.0 Hz, 0.4H), 5.88 and 5.83 (2s, 1H),3.87-2.89 ((m, 8H), 1.89 and 1.86 (2s, 6H) ppm.

Example 10 Synthesis ofN-(2-(4-chlorophenyl)propan-2-yl)-4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-amineA8

Compound A8 was synthesized in two steps according to the procedure forcompound A13, substituting 4-chlorobenzonitrile in place ofnaphthalene-2-carbonitrile. The crude product was purified bypreparative HPLC to give 125 mg (41% yield for 2 steps) of compound A8as a white solid: 99.5% purity (HPLC); MS m/z: 500.2 (M+1); ¹H NMR(CDCl₃, 500 MHz) δ 8.44 (d, J=8.0 Hz, 0.6H), 7.90 (d, J=7.5 Hz, 0.6H),7.80 (d, J=8.0 Hz, 0.4H), 7.65 (t, J_(HF)=54.0 Hz, 0.6H), 7.49-7.33 (m,4H), 7.33-7.27 ((m, 2H), 7.15-6.87 (m, 0.8H), 5.75 and 5.72 (2s, 1H),3.86 (m, 2H), 3.81 (m, 2H), 3.76 (m, 1H), 3.69 (m, 1H), 3.46 (m, 1H),3.30 (m, 1H), 1.79 and 1.76 (2s, 6H) ppm

Example 11 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-(4-methoxyphenyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA9

Compound A9 was synthesized in two steps according to the procedure forcompound A13, substituting 4-methoxybenzonitrile in place ofnaphthalene-2-carbonitrile. The crude compound A9 was purified bypreparative HPLC to give 150 mg (50% yield for 2 steps) of product as awhite solid: 98.0% purity (LCMS), MS m/z: 496.2 (M+1); ¹H NMR (CDCl₃,500 MHz) δ 8.44 (d, J=8.5 Hz, 0.5H), 7.90 (d, J=8.0 Hz, 0.5H), 7.80 (d,J=8.0 Hz, 0.5H), 7.65 (t, J_(HF)=53.5 Hz, 0.5H), 7.53 (d, J=8.5 Hz,0.5H), 7.47-7.33 (m, 3H), 7.31 (t, J=7.5 Hz, 0.5H), 7.16 (t, 0.1=7.5 Hz,0.5H), 6.95 (d, J=9.0 Hz, 1H), 6.85 (d, J=9.0 Hz, 1H), 6.85 (t,J_(HF)=53.0 Hz, 0.5H), 5.77 (d, J=8.5 Hz, 1H), 3.87 (m, 2H), 3.81 (m,5H), 3.76 (m, 1H), 3.69 (m, 1H), 3.48 (m, 1H), 3.40 (m, 1H), 1.79 and1.75 (2s, 6H) ppm.

Example 12 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(4-fluorophenyl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA22

A mixture of 1-(4-fluorophenyl)-2-methylpropan-2-amine (125 mg, 0.748mmol) and compound 1 (183 mg, 0.499 mmol) in dioxane (15 mL) wasrefluxed overnight. The volatiles were removed in vacuo and the residuewas purified by prep-HPLC to give4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(4-fluorophenyl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amine(35 mg, 14% yield) as a white solid: 98.1% purity (HPLC); MS m/z: 498.2(M+1); ¹H NMR (CDCl₃, 500 MHz) δ 8.37 (d, J=7.5 Hz, 1H), 7.88 (d, J=7.5Hz, 1H), 7.63 (t, J_(HF)=54.0 Hz, 1H), 7.41 (m, 2H), 7.04 (t, J=8.0 Hz,2H), 6.96 (t, J=8.5 Hz, 2H), 5.10 (s, 1H), 4.00-3.72 (m, 8H), 3.18 (s,2H), 1.45 (s, 6H) ppm.

Example 13 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-phenylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA14

To a mixture of 2-methyl-1-phenyl-2-propanol (1.5 g, 10 mmol) andacetonitrile (3 mL) in acetic acid (15 mL) was added concentratedsulfuric acid (3 mL) dropwise at room temperature. The mixture wasstirred at 65° C. for 3 hours and then poured into ice-water (ca. 200mL). The aqueous solution was basified with saturated aqueous sodiumhydroxide until pH >11. The suspension was stirred for further 0.5 hour,and then the precipitated solid was filtered and washed with water. Thewhite solid was air-dried to give N-(2-methyl-1-phenylpropan-2-yl)acetamide (1.5 g, 78% yield), which was used for the next step withoutfurther purification.

A mixture of N-(2-methyl-1-phenylpropan-2-yl) acetamide (191 mg, 1.00mmol) and potassium hydroxide (1 g) in ethylene glycol (10 mL) wasrefluxed for 8 hours. The mixture was diluted with ice-water andextracted with ethyl acetate. The combined organic fractions were washedwith water, dried over anhydrous sodium sulfate and concentrated invacuo to give crude 2-methyl-1-phenylpropan-amine (200 mg) as a brownoil, which was used for the next step without further purification.

Compound A14 was synthesized according to the procedure for compoundA22, substituting the crude 2-methyl-1-phenylpropan-amine in place of1-(4-fluorophenyl)-2-methylpropan-2-amine. The product was purified bypreparative HPLC to give compound A14 (30 mg, 13% yield for 2 steps) asa white solid: 96.4% purity (HPLC); MS m/z: 480.3 (M+1); ¹H NMR (CDCl₃,500 MHz) δ 8.39 (d, J=7.5 Hz, 1H), 7.90 (d, J=7.5 Hz, 1H), 7.65 (t,J_(HF)=54.0 Hz, 1H), 7.42 (m, 2H), 7.28 (m, 3H), 7.16-7.10 (m, 2H), 5.15(s, 1H), 4.01-3.75 (m, 8H), 3.22 (s, 2H), 1.49 (s, 6H) ppm.

Example 14 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(2-chlorophenyl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA16

A mixture of 1-(2-chlorophenyl)-2-methylpropan-2-amine hydrochloride(165 mg, 0.750 mmol), compound 1 (184 mg, 0.502 mmol) and potassiumcarbonate (138 mg, 1.00 mmol) in dioxane (15 mL) was refluxed for 12hours. The volatiles were removed in vacuo and the residue was purifiedby reverse phase flash chromatography (0 to 80% acetonitrile in aq. 0.5%ammonium bicarbonate) to give4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(2-chlorophenyl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amine(65 mg, 25% yield) as a white solid: 99.2% purity (HPLC); MS m/z: 514.2(M+1); ¹H NMR (CDCl₃, 500 MHz) δ 8.41 (d, J=8.0 Hz, 1H), 7.90 (d, J=7.0Hz, 1H), 7.66 (t, J_(HF)=53.5 Hz, 1H), 7.50-7.36 (m, 3H), 7.24-7.05 (m,3H), 5.34 (s, 1H), 4.05-3.70 (m, 8H), 3.43 (s, 2H), 1.53 (s, 6H) ppm.

Example 15 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(4-methoxyphenyl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA25

A mixture of 4-(hydroxymethyl)phenol (1.0 g, 8.1 mmol) and2-nitropropane (4.0 g, 45 mmol) in diglyme (50 mL) was cooled in an icebath. Potassium tert-butoxide (0.45 g, 4.0 mmol) was added in portions,then the reaction mixture was heated to reflux overnight. After cooling,the mixture was concentrated and the residue was purified by silica gelcolumn chromatography (petroleum ether/ethyl acetate) to give4-(2-methyl-2-nitropropyl)phenol (1.3 g, 83% yield) as a light yellowsolid.

Iodomethane (0.12 mL, 1.3 mmol) was added to a mixture of4-(2-methyl-2-nitropropyl)phenol (300 mg, 1.5 mmol) and potassiumcarbonate (425 mg, 3.1 mmol) in tetrahydrofuran (20 mL) andN,N-dimethylformamide (1 mL). After refluxing overnight, the mixture wascooled and concentrated under vacuum. The residue was dissolved in ethylacetate, washed with water, dried over anhydrous sodium sulfate andconcentrated to provide crude1-methoxy-4-(2-methyl-2-nitropropyl)benzene (200 mg, 62% yield) asyellow oil which was used directly in the next step.

The crude 1-methoxy-4-(2-methyl-2-nitropropyl)benzene (200 mg, 0.96mmol) was combined with palladium on carbon (40 mg) in methanol (30 mL).The suspension was vigorously stirred at room temperature under ahydrogen atmosphere overnight. The mixture was filtered through Celiteand the filtrate was concentrated to give1-(4-methoxyphenyl)-2-methylpropan-2-amine (150 mg, 88% yield) as ayellow oil which was used without further purification. (MS m/z: 180(M+1)).

A mixture of the 1-(4-methoxyphenyl)-2-methylpropan-2-amine (73 mg, 0.41mmol) and compound 1 (100 mg, 0.27 mmol) in dioxane (25 mL) was refluxedovernight. The volatiles were removed under vacuum and the residue waspurified by prep-HPLC to give compound A25 (40 mg, 29% yield) as a whitesolid: >99.5% purity (HPLC); MS m/z: 510.2 (M+1); ¹H NMR (CDCl₃, 500MHz) δ 8.38 (d, J=8.0 Hz, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.64 (t,J_(HF)=54.0 Hz, 1H), 7.41 (m, 2H), 7.01 (d, J=8.5 Hz, 2H), 6.82 (d,J=8.0 Hz, 2H), 5.10 (s, 1H), 3.93 (m, 3H), 3.83 (m, 5H), 3.77 (s, 3H),3.13 (s, 2H), 1.45 (s, 6H) ppm.

Example 16 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(2-methoxyphenyl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA19

Compound A19 was synthesized according to the procedure for compoundA16, substituting 1-(2-methoxyphenyl)-2-methylpropan-2-amine in place of1-(2-chlorophenyl)-2-methylpropan-2-amine hydrochloride. The product waspurified by reverse phase flash chromatography (0 to 80% acetonitrile inwater) to give compound A19 (66 mg, 81% yield) as a white solid: >99.5%purity (HPLC); MS m/z: 510.2 (M+1); ¹H NMR (CDCl₃, 500 MHz) δ 8.42 (dd,J=7.5 Hz and 1.5 Hz, 1H), 7.88 (dd, J=6.5 Hz and 2.5 Hz, 1H), 7.67 (t,J_(HF)=53.5 Hz, 1H), 7.39 (m, 2H), 7.26 (m, 2H), 7.12 (dd, J=7.5 Hz and1.5 Hz, 1H), 6.95 (m, 2H), 6.68 (s, 1H), 3.97 (s, 3H), 3.93-3.74 (m,8H), 3.04 (s, 2H), 1.56 (s, 6H) ppm.

Example 17 Synthesis ofN-(1-(4-bromophenyl)-2-methylpropan-2-yl)-4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-amineA24

Compound A24 was synthesized according to the procedure for compoundA16, substituting 1-(4-bromophenyl)-2-methylpropan-2-amine hydrochloridein place of 1-(2-chlorophenyl)-2-methylpropan-2-amine hydrochloride. Theproduct was purified by reverse phase flash chromatography (0 to 80%acetonitrile in water) which yielded compound A24 (110 mg, 39% yield) asa white solid: 98.6% purity (HPLC); MS m % z: 558.2 (M+1), 560.2 (M+3);1H NMR (CDCl₃, 500 MHz) δ 8.38 (d, J=7.5 Hz, 1H), 7.90 (d, J=7.5 Hz,1H), 7.65 (t, JHF=53.5 Hz, 1H), 7.52-7.38 (m, 4H), 6.97 (d, 2H), 5.07(s, 1H), 4.00-3.70 (m, 8H), 3.18 (s, 2H), 1.47 (s, 6H) ppm.

Example 18 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(o-tolyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA18

Compound A18 was synthesized according to the procedure for compoundA16, substituting 2-methyl-1-(o-tolyl)propan-2-amine hydrochloride inplace of 1-(2-chlorophenyl)-2-methylpropan-2-amine hydrochloride. Theproduct was purified by silica gel column chromatography (20% ethylacetate in petroleum ether) to give compound A18 (120 mg, 89% yield) asa white solid: >99.5% purity (HPLC); MS m/z: 494.2 (M+1); ¹H NMR (CDCl₃,500 MHz) δ 8.39 (d, J=8.0 Hz, 1H), 7.88 (d, J=7.0 Hz, 1H), 7.64 (t,J_(HF)=53.5, 1H), 7.40 (m, 2H), 7.22-6.98 (m, 4H), 5.24 (s, 1H),4.00-3.75 (m, 8H), 3.25 (s, 2H), 2.36 (s, 3H), 1.49 (s, 6H) ppm.

Example 19 Synthesis ofN-(1-(4-chlorophenyl)-2-methylpropan-2-yl)-4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-amineA23

Methylmagnesium bromide (3 M in ether, 5.5 mL, 16.5 mmol) was addeddropwise to a solution of methyl 4-chlorophenylacetate (1.0 g, 5.4 mmol)in tetrahydrofuran (20 mL) at 0° C. under a nitrogen atmosphere. Themixture was stirred at room temperature overnight and then quenched bythe addition of water (30 mL). The organic phase was washed with brine,dried over sodium sulfate and concentrated to give1-(4-chlorophenyl)-2-methylpropan-2-ol (1.0 g, 100% yield) as a yellowoil, which was used without further purification.

A solution of the crude alcohol (184 mg, 0.996 mmol) andchloroacetonitrile (150 mg, 1.99 mmol) in acetic acid (3.0 mL) wascooled to 0° C. Concentrated sulfuric acid (1.0 mL) was added to thesolution dropwise while keeping the reaction temperature below 10° C.After stirring at room temperature for 1 hour, the resulting solutionwas poured onto ice and basified by the addition of solid potassiumcarbonate to p1H>8. The mixture was extracted with ethyl acetate and thecombined organic fractions were washed with water, dried over sodiumsulfate and concentrated under vacuum to give 150 mg of2-chloro-N-(1-(4-chlorophenyl)-2-methylpropan-2-yl)acetamide as yellowsolid. The crude material was used directly in the next step.

To a mixture of2-chloro-N-(1-(4-chlorophenyl)-2-methylpropan-2-yl)acetamide (259 mg,1.00 mmol) in dioxane (5.0 mL) was added conc. hydrochloric acid (20mL). After stirring at 105° C. for 16 hours, the reaction mixture waspoured onto ice and basified by the addition of saturated aq. sodiumbicarbonate to pH>8. The mixture was extracted with ethyl acetate andthe combined organic fractions were washed with water, dried over sodiumsulfate and concentrated under vacuum. The crude product was thenpurified by reverse phase flash chromatography (0 to 25% acetonitrile inaq. 0.01% formic acid) to give 1-(4-chlorophenyl)-2-methylpropan-2-amine(70 mg, 38% yield) as a white solid.

A mixture of 1-(4-chlorophenyl)-2-methylpropan-2-amine (70 mg, 0.38mmol), compound 1 (93 mg, 0.25 mmol) and potassium carbonate (69 mg,0.50 mmol) in dioxane (10 mL) was refluxed overnight. The volatiles wereremoved under vacuum and the residue was purified by reverse phase flashchromatography (0 to 70% acetonitrile in aq. 0.01% ammonium bicarbonate)to give compound A23 (57 mg, 44% yield) as a white solid: 93.1% purity(HPLC); MS m/z: 514.1 (M+1); ¹H NMR (CDCl₃, 500 MHz) δ 8.37 (d, J=8.0Hz, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.63 (t, J_(HF)=54.0 Hz, 1H), 7.41 (m,2H), 7.25 (m, 2H), 7.18-6.90 (m, 2H), 5.05 (s, 1H), 4.00-3.72 (m, 8H),3.19 (s, 2H), 1.45 (s, 6H) ppm.

Example 20 Synthesis ofN-(1-(3-chlorophenyl)-2-methylpropan-2-yl)-4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-amineA20

Thionyl chloride (11 g, 100 mmol) was added dropwise to a mixture of3-chlorophenylacetic acid (1.7 g, 10 mmol) in methanol (20 mL) at 0° C.The resulting mixture was refluxed at 80° C. for 12 hours. The volatileswere removed under vacuum and the residue was diluted with water andextracted with ethyl acetate. The combined organic solution was washedwith water, dried over sodium sulfate and the concentrated to give 1.5 gof methyl 2-(3-chlorophenyl)acetate as a yellow oil, which was usedwithout further purification.

Compound A20 was synthesized in 4 steps according to the procedure forcompound A23, substituting the crude methyl 2-(3-chlorophenyl)acetate inplace of methyl 4-chlorophenylacetate. The final product was purified byreverse phase flash chromatography (0 to 70% acetonitrile in aq. 0.01%ammonium bicarbonate) to give 19 mg of compound A20 as a whitesolid: >99.5% purity (HPLC); MS m/z: 514.1 (M+1); ¹H NMR (CDCl₃, 500MHz) δ 8.37 (d, J=8.0 Hz, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.62 (t,J_(HF)=54.0 Hz, 1H), 7.41 (m, 2H), 7.21 (m, 2H), 7.10 (s, 1H), 6.96 (m,1H), 5.10 (s, 1H), 4.00-3.69 (m, 8H), 3.19 (s, 2H), 1.47 (s, 6H) ppm.

Example 21 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(3-methoxyphenyl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA21

Lithium diisopropylamide (2 M in tetrahydrofuran, 2.71 mL, 5.42 mmol)was added to a mixture of ethyl isobutyrate (600 mg, 5.17 mmol) intetrahydrofuran (60 mL) at −78° C. and stirred at this temperature for 1hour. 3-Methoxybenzyl chloride (1.15 g, 7.34 mmol) was added dropwiseand the reaction mixture was stirred at −78° C. for another 1 hour andthen at room temperature overnight. The mixture was quenched by waterand extracted with ethyl acetate. The combined organic fractions werewashed with water, dried over sodium sulfate and concentrated undervacuum to give ethyl-3-(3-methoxyphenyl)-2,2-dimethylpropanoate (1.3 g)as a yellow oil, which was used in the next step without furtherpurification.

The crude ethyl-3-(3-methoxyphenyl)-2,2-dimethylpropanoate (1.00 g, 4.23mmol) was taken up in a solution of ethanol (50 mL) and sodium hydroxide(2 N, 10 mL). The reaction mixture was refluxed overnight and thenconcentrated under vacuum. The concentrated aqueous solution wasacidified with hydrochloric acid (2 N) to pH 3-4 and extracted withethyl acetate. The combined organic fractions were dried over sodiumsulfate and evaporated to yield3-(3-methoxyphenyl)-2,2-dimethylpropanoic acid (600 mg) as a brown oil,which was used directly in the next step. MS m/z: 207 (M−1).

A mixture of 3-(3-methoxyphenyl)-2,2-dimethylpropanoic acid (200 mg,0.96 mmol) in acetone (40 mL) and water (4 mL) was cooled to 0° C.Triethyl amine (0.18 mL, 1.3 mmol) was added to the reaction mixturefollowed by methyl chloroformate (118 mg, 1.25 mmol). The mixture wasstirred for 1 hour at 0° C. and then another solution of sodium azide(94 mg, 1.45 mmol) in water (1 mL) was added dropwise. The reactionmixture was stirred at room temperature for another 1 hour. The mixturewas diluted with water and extracted with ethyl acetate. The combinedorganic fractions were washed with water, dried over sodium sulfate andconcentrated to give 3-(3-methoxyphenyl)-2,2-dimethylpropanoyl azide (60mg) as a crude yellow oil, which was used without further purification.

A mixture of the crude 3-(3-methoxyphenyl)-2,2-dimethylpropanoyl azide(160 mg, 0.69 mmol) in toluene (20 mL) was refluxed overnight. Thesolvent was removed under vacuum to give1,3-bis(1-(3-methoxyphenyl)-2-methylpropan-2-yl)urea (158 mg) as a brownoil, which was used without purification: MS m/z: 383 (M−1).

A mixture of the crude urea (80 mg, 0.21 mmol) and potassium hydroxide(32 mg, 0.57 mmol) in ethylene glycol (5 mL) was refluxed for 2 hours.The reaction mixture was diluted with water and extracted with ethylacetate. The combined organic fractions were washed with water, driedover sodium sulfate and concentrated to give1-(3-methoxyphenyl)-2-methylpropan-2-amine (75 mg) as a brown oil, whichwas used directly in the next step. MS m/z: 180 (M+1).

A mixture of the crude amine (63 mg, 0.35 mmol) and compound 1 (100 mg,0.27 mmol) in dioxane (25 mL) was refluxed overnight. The volatiles wereremoved in vacuo and the residue was purified by prep-HPLC to givecompound A21 (30 mg, 22% yield) as a white solid: >99.5% purity (HPLC);MS m/z: 510.2 (M+1); ¹H NMR (CDCl₃, 500 MHz) δ 8.37 (d, J=8.0 Hz, 1H),7.89 (d, J=7.5 Hz, 1H), 7.62 (t, J_(HF)=53.5 Hz, 1H), 7.40 (m, 2H), 7.20(t, J=7.5 Hz, 1H), 6.79 (dd, J=8.5 Hz & 2.0 Hz, 1H), 6.69 (d, J=7.5 Hz,1H), 6.65 (s, 1H), 5.14 (s, 1H), 4.00-3.76 (m, 8H), 3.74 (s, 3H), 3.17(s, 2H), 1.48 (s, 6H) ppm.

Example 22 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(naphthalen-2-yl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA26

Lithium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 25.3 mL, 25.3mmol) was added to a mixture of ethyl isobutyrate (2.67 g, 23.0 mmol) intetrahydrofuran (25 mL) at −78° C. After stirring for 30 m, a solutionof 2-(chloromethyl)naphthalene (400 mg, 2.30 mmol) in tetrahydrofuran(10 mL) was added to the reaction mixture dropwise. The mixture wasstirred at −78° C. for another hour and then at room temperatureovernight. The mixture was quenched by the addition of water andextracted with ethyl acetate. The combined organic fractions were washedwith water, dried over sodium sulfate and concentrated under vacuum togive ethyl 2,2-dimethyl-3-(naphthalene-2-yl)propanoate (1.00 g) as ayellow oil, which was used without further purification.

The crude ester (915 mg) was taken up in dioxane (4 mL) and 20% aqueoussodium hydroxide (8 mL). After stirring at room temperature for 2 hours,the reaction mixture was diluted with ethyl acetate. The aqueousfraction was acidified to pH=2 with concentrated hydrochloric acid andwas then extracted with ethyl acetate. The combined organic fractionswere dried over sodium sulfate and concentrated to yield2,2-dimethyl-3-(naphthalene-2-yl)propanoic acid (211 mg, 40% yield fortwo steps) as a white solid, which was used directly in the next step.

A mixture of the intermediate acid (211 mg, 0.920 mmol) in acetone (3mL) and water (0.3 mL) was cooled to 0° C. Triethyl amine (0.20 mL, 1.40mmol) was added to the reaction mixture followed by methyl chloroformate(104 mg, 1.10 mmol). The reaction was stirred at room temperature for 30minutes and a solution of sodium azide (120 mg, 1.84 mmol) in water (0.5mL) was added dropwise. After stirring at room temperature for 2 hours,the reaction mixture was diluted with water and extracted with petroleumether. The combined organic fractions were washed with water, dried oversodium sulfate and evaporated to give crude2,2-dimethyl-3-(naphthalene-2-yl)propanoyl azide (117 mg, 50% yield) asa colorless oil, which was used without further purification.

The crude acyl azide (117 mg, 0.46 mmol) was refluxed in toluene (3 mL)overnight to generate the intermediate isocyanate. The reaction mixturewas allowed to cooled to room temperature and a solution of 10%hydrochloric acid (3 mL) was added. After refluxing for 4 hours, thereaction mixture was concentrated under vacuum to give2-methyl-1-(naphthalene-2-yl)propan-2-amine (98 mg, 90% yield) as ayellow solid, which was used directly in the next step.

A mixture of the crude amine (98 mg, 0.42 mmol), compound 1 (103 mg,0.28 mmol) and potassium carbonate (116 mg, 0.84 mmol) in dioxane (3 mL)was refluxed overnight. The reaction mixture was concentrated and theresidue was purified by prep-HPLC to give compound A26 (12 mg, 8% yield)as a white solid: >99.5% purity (HPLC); MS m/z: 530.3 (M+1); ¹H NMR(CDCl₃, 500 MHz) δ 8.37 (d, J=8.0 Hz, 1H), 7.85-7.37 (m, 10H), 5.19 (s,1H), 4.04-3.75 (m, 8H), 3.37 (s, 2H), 1.53 (s, 6H) ppm.

Example 23 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(naphthalen-1-yl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA27

Methylmagnesium bromide (3 M in ether, 10 mL, 30 mmol) was addeddropwise to a solution of methyl naphthalene-1-acetate (2.0 g, 10 mmol)in tetrahydrofuran (20 m L) at 0° C. under a nitrogen atmosphere. Afterstirring at room temperature overnight, the reaction mixtures wasquenched by the addition of water. The organic fraction was washed withbrine, dried over sodium sulfate and concentrated under vacuum to givecrude 2-methyl-1-(naphthalene-1-yl)propan-2-ol (2.0 g) as a yellow oil,which was used directly in the next step.

The crude alcohol (2.0 g, 10 mmol) was dissolved in acetonitrile (10 mL)and concentrated sulfuric acid (4.9 g, 50 mmol) was added dropwise at 0°C. After stirring at room temperature for 2 hours, the reaction mixturewas diluted with water and extracted with dichloromethane. The combinedorganic fractions were dried over sodium sulfate and evaporated. Theresidue was purified by silical gel column chromatography (petroleumether/ethyl acetate) to giveN-(2-methyl-1-(naphthalene-1-yl)propan-2-yl)acetamide (0.90 g, 37%yield) as a yellow solid.

Concentrated hydrochloric acid (10 mL) was added to a solution of theintermediate acetamide (0.20 g, 0.83 mmol) in dioxane (2 mL) and theresulting mixture was refluxed for 3 days. After cooling to roomtemperature, the reaction mixture was basified to pH 9 by the additionof solid sodium bicarbonate. The mixture was extracted with ethylacetate and the combined organic fractions were dried over sodiumsulfate and concentrated to give crude2-methyl-1-(naphthalene-1-yl)propan-2-amine (0.15 g, 23% yield) as ayellow oil, which was used without further purification.

The crude amine (153 mg, 0.25 mmol), compound 1 (48 mg, 0.13 mmol) andpotassium carbonate (36 mg, 0.25 mmol) were taken up in dioxane (2 mL)and heated to reflux overnight. The reaction mixture was concentratedunder vacuum and the residue was purified by prep-HPLC to give compoundA27 (16 mg, 23% yield) as a white solid: >99.5% purity (HPLC); MS m/z:530.3 (M+1); ¹H NMR (CDCl₃, 500 MHz) δ 8.29 (d, J=8.0 Hz, 1H), 8.15 (d,J=7.0 Hz, 1H), 7.88 (d, J=6.5 Hz, 2H), 7.77 (d, J=8.0 Hz, 1H), 7.56 (t,J_(HF)=54.0 Hz, 1H), 7.48 (m, 2H), 7.39 (m, 3H), 7.27 (d, J=7.0 Hz, 1H),5.29 (s, 1H), 4.02-3.73 (m, 8H), 3.66 (s, 2H), 1.54 (s, 6H) ppm.

Example 24 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(2-fluorophenyl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA15

Compound A15 was synthesized in 6 steps according to the procedure forcompound A21, substituting 2-fluorobenzyl bromide in place of3-methoxybenzyl chloride. The final product was purified by prep-HPLC togive compound A15 (30 mg, 22% yield) as a white solid: 99.4% purity(HPLC); MS m/z: 498.2 (M+1); ¹H NMR (CDCl₃, 500 MHz) δ 8.39 (d, J=8.0Hz, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.65 (t, J_(HF)=53.5 Hz, 1H), 7.41 (m,2H), 7.22 (m, 1H), 7.06 (m, 3H), 5.25 (s, 1H), 4.00-3.73 (m, 8H), 3.28(s, 2H), 1.49 (s, 6H) ppm.

Example 25 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-2-phenylpropyl)-6-morpholino-1,3,5-triazin-2-amineA29

Powdered lithium aluminum hydride (137 mg, 3.61 mmol) was addedportionwise to a solution of 2-methyl-2-phenylpropanenitrile (436 mg,3.00 mmol) in tetrahydrofuran (20 mL). The resulting mixture was stirredat 80° C. overnight. The reaction was then cooled to 0° C. and water (66μL, 3.7 mmol), 10% sodium hydroxide (1.44 g, 3.6 mmol) and water (195μL, 10.8 mmol), respectively, were added dropwise into the reactionmixture. The suspension was filtered through anhydrous magnesium sulfateand the solution was concentrated under vacuum to give2-methyl-2-phenylpropan-1-amine (400 mg) as a yellow oil, which was usedfor the next step without further purification.

The crude amine (400 mg, 2.7 mmol) and compound 1 (147 mg, 0.401 mmol)were refluxed in dioxane (25 mL) for 4 hours. After cooling, thereaction mixture was concentrated under vacuum. The residue was dilutedwith saturated sodium bicarbonate and extracted with ethyl acetate. Thecombined organic fractions were washed with water and brine, dried oversodium sulfate and concentrated. The crude product was purified byprep-HPLC to give compound A29 (75 mg, 35% yield for 2 steps) as a whitesolid: >99.5% purity (HPLC); MS m/z: 480.2 (M+1); ¹H NMR (CDCl₃, 500MHz) (rotamers) δ 8.45 (d, J=7.5 Hz, 0.5H), 8.33 (d, J=8.0 Hz, 0.5H),7.92 (d, J=7.5 Hz, 0.5H), 7.88 (d, J=7.5 Hz, 0.5H), 7.64 and 7.60 (2t,J_(HF)=53.5 Hz, 1H), 7.42 (m, 6H), 7.28 (m, 1H), 5.13-5.00 (m, 1H),4.00-3.70 (m, 10H), 1.45 and 1.44 (2s, 6H) ppm.

Example 26 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-(1-phenylcyclopropyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA30

Methylmagnesium bromide (3.0 M in tetrahydrofuran, 3.0 mL, 9.0 mmol) wasadded to a solution of 1-phenyl-1-cyclopropanecarbonitrile (429 mg, 3.0mmol) in anhydrous tetrahydrofuran (4 mL) at room temperature under anitrogen atmosphere. The reaction mixture was heated to 100° C. for 10minutes in a microwave oven. Then titanium(IV) isopropoxide (0.9 mL, 3.0mmol) was added and the reaction mixture was heated to 50° C. for 1 hourin the microwave. After cooling, a solution of 25% aqueous ammonia (2mL) was added dropwise to the reaction mixture. The suspension wasfiltered through a Celite pad which was washed with tetrahydrofuran. Thecombined filtrate was diluted with water and extracted with ethylacetate. The combined organic extracts were dried over anhydrous sodiumsulfate and concentrated under vacuum to give2-(1-phenylcyclopropyl)propan-2-amine (400 mg) as a crude yellow oil: MSm/z: 178 (M+1).

The crude amine (200 mg, 1.1 mmol) was combined with compound 1 (100 mg,0.27 mmol) and potassium carbonate (150 mg, 1.1 mmol) in dioxane (20 mL)and heated to reflux overnight. The mixture was diluted with water andextracted with ethyl acetate. The organic extracts were dried withanhydrous sodium sulfate and concentrated under vacuum. The crudeproduct was purified by reversed phase flash chromatography (0 to 85%acetonitrile in 0.01% ammonium bicarbonate) to give compound A30 (46 mg34% yield) as a white solid: 94.4% purity (HPLC); MS m/z: 506.2 (M+1):¹H NMR (CDCl₃, 500 MHz) δ 8.34 (d, J=7.5 Hz, 1H), 7.90 (d, J=7.5 Hz,1H), 7.61 (t, J_(HF)=54.0 Hz, 1H), 7.42 (m, 2H), 7.35 (m, 2H), 7.29 (m,2H), 7.24 (m, 1H), 5.26 (s, 1H), 4.00-3.65 (m, 8H), 1.48 (s, 6H), 1.17(m, 2H), 0.84 (m, 2H) ppm.

Example 27 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(2-bromophenyl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA17

Lithium diisopropylamide (2M in hexane, 1.5 mL, 3.0 mmol) was added to asolution of ethyl isobutyrate (233 mg, 2.01 mmol) in tetrahydrofuran (1mL) at −78° C. and the reaction mixture was stirred at this temperaturefor 30 min. Then, a solution of 2-bromobenzyl bromide (250 mg, 1.00mmol) in tetrahydrofuran (1 mL) was added dropwise. The reaction mixturewas stirred at −78° C. for another 1 hr and then at room temperatureovernight. The mixture was diluted with water and extracted with ethylacetate. The combined organic fractions were washed with water, driedover sodium sulfate, and concentrated to give 482 mg of ethyl3-(2-bromophenyl)-2,2-dimethylpropanoate as a yellow oil. The crudeintermediate was used directly in the next step.

A solution of the crude ester (482 mg) in dioxane (2 mL) was combinedwith aqueous sodium hydroxide (20%, 4 mL) and stirred at roomtemperature for 2 hrs. The reaction mixture was diluted with ethylacetate and the aqueous fraction was acidified to pH 2 with conc.hydrochloric acid. After extraction with ethyl acetate, the combinedorganic fractions were dried over sodium sulfate and concentrated undervacuum to give 121 mg (47% yield for two steps) of3-(2-bromophenyl)-2,2-dimethylpropanoic acid as a white solid. The crudecarboxylic acid was used in the next step without further purification:MS m/z: 255.0 (M−1).

Triethylamine (112 mg, 1.11 mmol) was added to a mixture of theintermediate carboxylic acid (188 mg, 0.731 mmol) in acetone (8 mL) andwater (1 mL). The reaction mixture was cooled to 0° C. and methylchloroformate (84 mg, 0.88 mmol) was added. The mixture was stirred atroom temperature for 30 min and then a solution of sodium azide (95 mg,1.46 mmol) in water (0.5 mL) was added dropwise. After stirring at roomtemperature overnight, the resulting mixture was diluted with water andextracted with petroleum ether. The combined organic factions werewashed with water, dried over sodium sulfate, and concentrated to give162 mg (79% yield) of 3-(2-bromophenyl)-2,2-dimethylpropanoyl azide as awhite solid, which was used directly in the next step: MS m/z: 252.9(M−28).

A solution of the crude acyl azide (162 mg, 0.574 mmol) in toluene (3mL) was refluxed overnight to give1-bromo-2-(2-isocyanato-2-methylpropyl)benzene. Then, the solution wascooled to room temperature and 10% aq. hydrochloric acid (3 mL) wasadded. The resulting mixture was refluxed for 4 hrs. The volatiles wereremoved in vacuo to give 129 mg (85% yield) of1-(2-bromophenyl)-2-methylpropan-2-amine hydrochloride as a white solid.The crude amine hydrochloride salt was used in the next step withoutfurther purification: MS m/z: 228.1 (M+1).

A mixture of the amine salt (129 mg, 0.49 mmol), compound 1 (121 mg,0.33 mmol), and potassium carbonate (183 mg, 1.33 mmol) was refluxed indioxane (4 mL) overnight. The volatiles were removed under vacuum andthe residue was purified by silical gel column chromatography (9% ethylacetate in petroleum ether) to give 99 mg (54% yield) of compound A 17,4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(2-bromophenyl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amine,as a white solid: >99.5% purity (HPLC); MS m/z: 558.2 (M+1), 560.2(M+3); ¹H NMR (CDCl₃, 500 MHz) δ 8.42 (d, 1H), 7.91 (d, 1H), 7.67 (t,1H), 7.60 (d, 1H), 7.48-7.37 (m, 2H), 7.22 (t, 1H), 7.11 (m, 2H), 5.32(s, 1H), 4.01-3.76 (m, 8H), 3.46 (s, 2H), 1.54 (s, 6H) ppm.

Example 28 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(pyridin-4-yl)phenyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA33

Compound A17 (200 mg, 0.358 mmol), pyridinyl-4-boronic acid (49 mg, 0.40mmol), sodium carbonate (114 mg. 1.08 mmol), and1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (29 mg, 0.036 mmol) were taken up inN,N′-dimethylformamide (4 m L) and water (1 m L) and stirred undernitrogen at 100° C. overnight. The reaction mixture was diluted withethyl acetate and filtered through Celite. The filtrate was washed withwater and brine, dried over sodium sulfate, and concentrated. The crudeproduct was purified by prep-HPLC to give 18 mg (9% yield) of compoundA33,4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(pyridin-4-yl)phenyl)-propan-2-yl)-6-morpholino-1,3,5-triazin-2-amine,as a white solid: >99.5% purity (HPLC); MS m/z: 557.3 (M+1); ¹H NMR(CDCl₃, 500 MHz)(rotamers) δ 8.53 (br s, 2H), 8.39 (d, 1H), 7.92 (d,1H), 7.66 (t, 1H), 7.49-7.38 (m, 2H), 7.34 (m, 2H), 7.26 (m, 1H),7.23-7.15 (m, 3H), 4.88 (s, 1H), 3.95-3.75 (m, 8H), 3.35 (s, 2H), 1.28(s, 6H) ppm.

Example 29 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(biphenyl-2-yl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA47

Compound A17 (140 mg, 0.251 mmol), phenylboronic acid (61 mg, 0.500mmol), sodium carbonate (80 mg, 0.755 mmol), and1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (21 mg, 0.0257 mmol) were taken up inN,N′-dimethylformamide (8 mL) and water (2 mL) and stirred undernitrogen at 100° C. overnight. The reaction mixture was diluted withethyl acetate and filtered through Celite. The filtrate was washed withwater and brine, dried over sodium sulfate, and concentrated. The crudeproduct was purified by chiral-SFC to give 60 mg (44% yield) of compoundA47,4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(biphenyl-2-yl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amine,as a white solid: >99.5% purity (HPLC); MS m/z: 556.2 (M+); ¹H NMR(CDCl₃, 500 MHz)(rotamers) δ 8.39 (d, 1H), 7.92 (d, 1H), 7.66 (t, 1H),7.44 (m, 2H), 7.28 (m, 7H), 7.22 ((m, 2H), 4.94 (s, 1H), 3.92-3.55 (m,8H), 3.37 (s, 2H), 1.28 (s, 6H) ppm.

Example 30 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(3-fluorophenyl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA39

Compound A39 was synthesized in 6 steps according to the procedure forA21, substituting 3-fluorobenzyl bromide in place of 3-methoxybenzylchloride. The final product was purified by prep-HPLC to give compoundA39 (35 mg) as a white solid: 99% purity (HPLC); MS m/z: 498.2 (M+1); ¹HNMR (DMSO_(d6), 500 MHz) δ 8.60 (d, 1H), 8.01 (t, 1H), 7.84 (d, 1H),7.54 (s, 1H), 7.45 (m, 2H), 7.30 (m, 1H), 7.03 (m, 1H), 6.94 (m, 2H),3.85 (m, 4H), 3.75 (m, 4H), 3.25 (s, 2H), 1.40 (s, 6H) ppm.

Example 31 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-m-tolylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA49

Compound A49 was synthesized in 6 steps according to the procedure forA21, substituting 3-methylbenzyl bromide in place of 3-methoxybenzylchloride. The final product was purified by prep-HPLC to give compoundA49 (15 mg) as a white solid: 98% purity (HPLC); MS m/z: 494.2 (M+1); ¹HNMR (CDCl₃, 500 MHz) δ 8.38 (d, 1H), 7.90 (d, 1H), 7.64 (t, 1H), 7.48(s, 1H), 7.42 (m, 1H), 7.19 (t, 1H), 7.10-6.88 (m, 3H), 5.17 (s, 1H),4.10-3.80 (m, 8H), 3.16 (s, 2H), 2.31 (s, 3H), 1.49 (s, 6H) ppm.

Example 32 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(4-fluoro-3-methoxyphenyl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA50

Compound A50 was synthesized in 6 steps according to the procedure forA21, substituting 4-fluoro-3-methoxybenzyl in place of 3-methoxybenzylchloride. The final product was purified by prep-HPLC to give compoundA50 (115 mg) as a white solid: 99% purity (HPLC); MS m/z: 528.2 (M+1);¹H NMR (CDCl₃, 500 MHz) δ 8.37 (d, 1H), 7.90 (d, 1H), 7.64 (t, 1H), 7.43(m, 2H), 6.99 (m, 1H), 6.71-6.60 (m, 2H), 5.12 (s, 1H), 4.01-3.78 (m,8H), 3.77 (s, 3H), 3.17 (s, 2H), 1.49 (s, 6H) ppm.

Example 33 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(2,4-difluorophenyl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA51

Compound A51 was synthesized in 5 steps according to the procedure forA20, substituting 2,4-difluorophenylacetic acid in place of3-chlorophenylacetic acid. The final product was purified by prep-HPLCto give compound A51 (60 mg) as a white solid: 99% purity (HPLC); MSm/z: 516.2 (M+1); ¹H NMR (CDCl₃, 500 MHz) δ 8.40 (d, 1H), 7.90 (d, 1H),7.65 (t, 1H), 7.43 (m, 2H), 7.04 (m, 1H), 6.84 (m, 2H), 5.19 (s, 1H),4.00-3.75 (m, 8H), 3.26 (s, 2H), 1.49 (s, 6H) ppm.

Example 34 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(2,6-difluorophenyl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA52

Compound A52 was synthesized in 5 steps according to the procedure forA20, substituting 2,6-difluorophenylacetic acid in place of3-chlorophenylacetic acid. The final product was purified by prep-HPLCto give compound A52 (38 mg) as a white solid: 98% purity (HPLC); MSm/z: 516.3 (M+1); ¹H NMR (CDCl₃, 500 MHz) δ 8.41 (d, 1H), 7.90 (d, 1H),7.66 (t, 1H), 7.43 (m, 2H), 7.23 (m, 1H), 6.91 (t, 2H), 5.43 (s, 1H),4.05-3.70 (m, 8H), 3.33 (s, 2H), 1.53 (s, 6H) ppm.

Example 35 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(pyridin-3-yl)phenyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA40

Compound A40 was synthesized according to the procedure for A33,substituting 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine inplace of pyridinyl-4-boronic acid. The crude product was purified byprep-HPLC to give compound A40 (41 mg, 41% yield) as a white solid: 98%purity (HPLC); MS m/z: 557.3 (M+1); ¹H NMR (DMSO_(d6), 500 MHz) δ 8.58(d, 1H), 8.40 (s, 1H), 8.37 (dd, 1H), 8.01 (t, 1H), 7.84 (d, 1H), 7.58(dd, 1H), 7.48 (t, 1H), 7.43 (t, 1H), 7.40-7.28 (m, 3H), 7.19 (s, 1H),7.13 (m, 2H), 3.82-3.60 (m, 8H), 3.34 (s, 2H), 1.23 (s, 6H) ppm.

Example 36 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(2-(2-methoxypyridin-4-yl)phenyl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA41

Compound A41 was synthesized according to the procedure for A33,substituting 2-methoxypyridine-4-boronic acid in place ofpyridinyl-4-boronic acid. The crude product was purified by prep-HPLC togive compound A41 (250 mg, 24% yield) as a white solid: 95% purity(HPLC); MS m/z: 587.3 (M+1); ¹H NMR (CDCl₃, 500 MHz) δ 8.40 (d, J=8.0Hz, 1H), 8.06 (d, 1H), 7.91 (d, 1H), 7.65 (t, 1H), 7.43 (m, 2H), 7.33(m, 2H), 7.25 (t, 1H), 7.16 (d, 1H), 6.78 (d, 1H), 6.62 (s, 1H), 4.85(s, 1H), 3.95-3.75 (m, 8H), 3.74 (s, 3H), 3.36 (s, 2H), 1.32 (s, 6H)ppm.

Example 37 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(2-methylpyridin-4-yl)phenyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA43

Compound A43 was synthesized according to the procedure for A33,substituting 2-methylpyridine-4-boronic acid in place ofpyridinyl-4-boronic acid. The crude product was purified by prep-HPLC togive compound A43 (15 mg, 24% yield) as a white solid: 98% purity(HPLC); MS m/z: 571.2 (M+1); ¹H NMR (CDCl₃, 500 MHz) δ 8.45 (d, 1H),8.40 (d, 1H), 7.91 (d, 1H), 7.66 (t, 1H), 7.44 (m, 2H), 7.33 (m, 2H),7.24 (m, 1H), 7.16 (m, 1H), 7.13-6.95 (m, 2H), 4.88 (s, 1H), 4.00-3.75(m, 8H), 3.36 (s, 2H), 2.49 (s, 3H), 1.28 (s, 6H)ppm.

Example 38 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(2-(1H-pyrazol-4-yl)phenyl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA44

Compound A44 was synthesized according to the procedure for A33,substituting 1-Boc-pyrazole-4-boronic acid pinacol ester in place ofpyridinyl-4-boronic acid. The crude product was purified by prep-HPLC togive compound A44 (15 mg, 31% yield) as a white solid: 99% purity(HPLC); MS m/z: 546.3 (M+1); ¹H NMR (DMSO_(d)s, 500 MHz) δ 12.84 (s,1H), 8.59 (d, 1H), 8.00 (t, 1H), 7.84 (d, 1H), 7.74 (br s, 1H), 7.50 (brs, 1H), 7.48 (t, 1H), 7.42 (t, 1H), 7.37 (s, 1H), 7.20 (m, 4H),3.85-3.42 (m, 8H), 3.42 (s, 2H), 1.21 (s, 6H)ppm.

Example 39 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA45

Compound A45 was synthesized according to the procedure for A33,substituting 1-methyl-1H-pyrazole-4-boronic acid pinacol ester in placeof pyridinyl-4-boronic acid. The crude product was purified by prep-HPLCto give compound A45 (35 mg, 12% yield) as a white solid: 98% purity(HPLC); MS m/z: 560.3 (M+1); ¹H NMR (CDCl₃, 500 MHz) δ 8.38 (d, 1H),7.91 (d, 1H), 7.65 (t, 1H), 7.51 (s, 1H), 7.48-7.37 ((m, 2H), 7.34 (s,1H), 7.28-7.17 (m, 4H), 5.04 (s, 1H), 3.95-3.78 (m, 11H), 3.40 (s, 2H),1.35 (s, 6H) ppm.

Example 40 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(1-methyl-1H-pyrazol-5-yl)phenyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA46

Compound A46 was synthesized according to the procedure for A33,substituting 1-methyl-1H-pyrazole-5-boronic acid pinacol ester in placeof pyridinyl-4-boronic acid. The crude product was purified by prep-HPLCto give compound A46 (7 mg, 4% yield) as a white solid: 98% purity(HPLC); MS m/z: 560.3 (M+1); ¹H NMR (CDCl₃, 500 MHz) δ 8.40 (d, 1H),7.91 (d, 1H), 7.67 (t, 1H), 7.50-7.30 (m, 5H), 7.24 (t, 2H), 6.21 (s,1H), 5.03 (s, 1H), 3.96-3.75 (m, 8H), 3.65 (s, 3H), 3.21 (s, 2H), 1.32(s, 6H) ppm.

Example 41 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(2′-fluorobiphenyl-2-yl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA59

Compound A59 was synthesized according to the procedure for A33,substituting 2-fluorophenylboronic acid in place of pyridinyl-4-boronicacid. The crude product was purified by prep-HPLC to give compound A59(73 mg, 71% yield) as a white solid: 99% purity (HPLC); MS m/z: 574.2(M+1); ¹H NMR (DMSO_(d6), 500 MHz) δ 8.61 (d, 1H), 8.02 (t, 1H), 7.84(d, 1H), 7.48 (t, 1H), 7.43 (t, 1H), 7.39-7.22 (m, 5H), 7.22 (t, 1H),7.14 (m, 2H), 6.97 (t, 1H), 3.74 (m, 8H), 3.30 (d, 1H), 3.14 (d, 1H),1.20 (s, 3H), 1.17 (s, 3H) ppm.

Example 42 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2′-methylbiphenyl-2-yl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA60

Compound A60 was synthesized according to the procedure for A33,substituting 2-methylphenylboronic acid in place of pyridinyl-4-boronicacid. The crude product was purified by prep-HPLC to give compound A60(120 mg, 47% yield) as a white solid: 99% purity (HPLC); MS m/z: 570.3(M+1); ¹H NMR (CDCl₃, 500 MHz) δ 8.42 (d, 1H), 7.92 (d, 1H), 7.68 (t,1H), 7.44 (m, 2H), 7.35-6.95 (m, 8H), 5.01 (s, 1H), 4.10-3.70 (m, 8H),3.30 (d, 1H), 2.99 (d, 1H), 2.06 (s, 3H), 1.36 (s, 3H), 1.30 (s, 3H)ppm.

Example 43 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(6′-chlorobiphenyl-2-yl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA61

Compound A61 was synthesized according to the procedure for A332substituting 2-chlorophenylboronic acid in place of pyridinyl-4-boronicacid. The crude product was purified by prep-HPLC to give compound A61(88 mg, 55% yield) as a white solid: 99% purity (HPLC); MS m/z: 590.2(M+1); ¹H NMR (CDCl₃, 500 MHz) δ 7.92 (d, 1H), 7.67 (t, 1H), 7.44 (m,2H), 7.33 (m, 3H), 7.27-7.00 (m, 5H), 4.96 (s, 1H), 4.00-3.75 (m, 8H),3.24 (d, 2H), 1.33 (s, 6H) ppm.

Example 44 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(6′-chlorobiphenyl-2-yl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA62

Compound A62 was synthesized according to the procedure for A33,substituting 2-fluoro-3-pyridinylboronic acid in place ofpyridinyl-4-boronic acid. The crude product was purified by prep-HPLC togive compound A62 (134 mg, 65% yield) as a white solid: 96% purity(HPLC); MS m/z: 575.3 (M+1); ¹H NMR (CDCl₃, 500 MHz) δ 8.38 (d, 1H),8.05 (d, 1H), 7.92 (d, 1H), 7.66 (t, 1H), 7.62 (m, 1H), 7.49-7.32 (m,4H), 7.28 (d, 1H), 7.15 (d, 1H), 6.91 (t, 1H), 4.80 (s, 1H), 4.05-3.70(m, 8H), 3.60 (d, 1H), 2.99 (d, 1H), 1.42 (s, 3H), 1.27 (s, 3H) ppm.

Example 45 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(pyrimidin-5-yl)phenyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA63

Compound A63 was synthesized according to the procedure forA33=substituting pyrimidine-5-boronic acid pinacol ester in place ofpyridinyl-4-boronic acid. The crude product was purified by prep-HPLC togive compound A63 (75 mg, 50% yield) as a white solid: 98% purity(HPLC); MS m/z: 558.3 (M+1); ¹H NMR (CDCl₃, 500 MHz) δ 9.05 (s, 1H),8.62 (s, 2H), 8.36 (d, 1H), 7.90 (d, 1H), 7.65 (t, 1H), 7.50-7.27 (m,5H), 7.16 (d, 1H), 4.86 (s, 1H), 3.95-3.80 (m, 8H), 3.34 (s, 2H), 1.32(s, 6H) ppm.

Example 46 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)phenyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amine

Compound A64 was synthesized according to the procedure for A33:substituting 2-(4-methylpiperazin-1-yl)pyridine-4-boronic acid pinacolester in place of pyridinyl-4-boronic acid. The crude product waspurified by prep-HPLC to give compound A64 (24 mg, 20% yield) as a whitesolid: 98% purity (HPLC); MS m/z: 655.4 (M+1); ¹H NMR (DMSO_(d6), 500MHz) δ 8.58 (d, 1H), 7.99 (t, 1H), 7.96 (d, 1H), 7.84 (d, 1H), 7.48 (t,1H), 7.43 (t, 1H), 7.37 (d, 1H), 7.35-7.22 (m, 3H), 7.21 (s, 1H), 7.07(d, 1H), 6.58 (d, 1H), 3.82-3.62 ((m, 8H), 3.37 (s, 2H), 3.26 (br s,4H), 2.25 (br s, 4H), 2.16 (s, 3H), 1.23 (s, 6H) ppm.

Example 47 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(3′-(morpholinomethyl)biphenyl-2-yl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA65

Compound A65 was synthesized according to the procedure for A33,substituting 3-(morpholinomethyl)phenylboronic acid pinacol ester inplace of pyridinyl-4-boronic acid. The crude product was purified byprep-HPLC to give compound A65 (40 mg, 17% yield) as a white solid: 99%purity (HPLC); MS m/z: 655.3 (M+1); ¹H NMR (CDCl₃, 500 MHz) δ 8.39 (d,1H), 7.91 (d, 1H), 7.64 (t, 1H), 7.43 (m, 2H), 7.35-7.10 (m, 8H), 4.97(s, 1H), 3.93-3.74 ((m, 8H), 3.68 (m, 4H), 3.50-3.32 (m, 4H), 2.38 (m,4H), 1.23 (s, 6H) ppm.

Example 48 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(3′-methoxybiphenyl-2-yl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA66

Compound A66 was synthesized according to the procedure for A33,substituting 3-methoxyphenylboronic acid in place of pyridinyl-4-boronicacid. The crude product was purified by prep-HPLC to give compound A66(18 mg, 11% yield) as a white solid: 99% purity (HPLC); MS m/z: 586.3(M+1); ¹H NMR (CDCl₃, 500 MHz) δ 8.39 (d, 1H), 7.91 (d, 1H), 7.65 (t,1H), 7.43 (m, 2H), 7.29 (m, 2H), 7.27-7.17 (m, 3H), 6.88-6.70 (m, 3H),4.90 (s, 1H), 3.95-3.75 (m, 8H), 3.55 (s, 1H) 3.38 (s, 2H), 1.32 (s, 6H)ppm.

Example 49 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(4′-methoxybiphenyl-2-yl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA67

Compound A67 was synthesized according to the procedure forA33=substituting 4-methoxyphenylboronic acid in place ofpyridinyl-4-boronic acid. The crude product was purified by prep-HPLC togive compound A67 (83 mg, 39% yield) as a white solid: 99% purity(HPLC); MS m/z: 586.2 (M+1); ¹H NMR (DMSO₆, 500 MHz) δ 8.61 (d, 1H),7.85 (t, 1H), 7.84 (d, 1H), 7.49 (t, 1H), 7.43 (t, 1H), 7.30-7.19 (m,4H), 7.08-7.02 (m, 3H), 6.73 (d, 2H), 3.82-3.63 (m, 8H), 3.62 (s, 3H),3.34 (s, 2H), 1.21 (s, 6H) ppm.

Example 50 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(piperidin-4-yl)phenyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA68

tert-Butyl4-(2-(2-((4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)amino)-2-methylpropyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylatewas synthesized according to the procedure for A33, substitutingN-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester in placeof pyridinyl-4-boronic acid. The crude product was purified by flashchromatography to give tert-butyl4-(2-(2-((4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)amino)-2-methylpropyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate(270 mg, 81% yield) as a white solid: MS m/z: 586.2 (M+1).

A mixture of the Boc-protected dihydropyridine (215 mg, 0.325 mmol) and10% palladium/carbon (22 mg) in methanol was stirred under a hydrogenatmosphere at 50° C. for 3 hrs. The reaction mixture was filteredthrough Celite. The filtrate was then concentrated and the residue waspurified by flash chromatography to give 70 mg (33% yield) of tert-butyl4-(2-(2-((4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)amino)-2-methylpropyl)phenyl)piperidine-1-carboxylateas a white solid. MS mi: 663 (M+1).

A mixture of the Boc-piperidine intermediate (65 mg. 0.098 mmol) andtrifluoroacetic acid (2 mL) in dichloromethane (2 mL) was stirred atroom temperature for 2 hrs. The volatiles were removed under reducedpressure. The residue was diluted with water and basified at 0° C. with1M sodium hydroxide to pH ˜8 and extracted with dichloromethane. Thecombined extracts were dried over sodium sulfate and concentrated. Thecrude product was purified by prep-HPLC to give compound A68 (12 mg, 22%yield) as a white solid: 98% purity (HPLC); MS m/z: 563.3 (M+1); ¹H NMR(CDCl₃, 500 MHz) δ 8.37 (d, 1H), 7.89 (d, 1H), 7.66 (t, 1H), 7.41 (m,2H), 7.33 (d, 1H), 7.28 (t, 1H), 7.16 (t, 1H), 7.07 (d, 1H), 5.16 (s,1H), 4.00-3.70 (m, 8H), 3.37 (m, 2H), 3.23 (s, 2H), 3.04 (m, 2H), 2.76(m, 2H), 2.03 (m, 2H), 1.80 (m, 2H), 1.52 (s, 6H) ppm.

Example 51 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(1-methylpiperidin-4-yl)phenyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA35

A mixture of compound A35 (80 mg, 0.14 mmol), aq. formaldehyde (37%, 23mg), and sodium cyanoborohydride (11 mg, 0.17 mmol) in methanol (2 mL)was stirred at room temperature for 1 hr. The crude product was purifiedby prep-HPLC to give compound A35 (11 mg, 13% yield) as a white solid:99% purity (HPLC); MS m/z: 577.3 (M+1); ¹H NMR (CDCl₃, 500 MHz) δ 8.37(d, 1H), 7.90 (d, 1H), 7.64 (t, 1H), 7.42 ((m, 2H), 7.32 (d, 1H), 7.24(t, 1H), 7.13 (t, 1H), 7.07 (d, 1H), 5.15 (s, 1H), 4.00-3.70 (m, 8H),3.28 (s, 2H), 2.94 (m, 2H), 2.78 (m, 2H), 2.28 (s, 3H), 1.89-1.60 (m,6H), 1.53 (s, 6H) ppm.

Example 52 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(2-(1-ethylpiperidin-4-yl)phenyl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA70

A mixture of compound A68 (0.14 g, 0.25 mmol), sodium cyanoborohydride(19 mg, 0.30 mmol), 40% aq. acetaldehyde (2 mL), anddiisopropylethylamine (0.16 g, 1.2 mmol) in acetonitrile (10 mL) wasstirred at room temperature for 1 hr. The reaction mixture wasconcentrated under vacuum and the residue was purified by prep-HPLC togive compound A70 (35 mg, 24% yield) as a white solid: 99% purity (HPLC); MS m/z: 591.3 (M+1); ¹H NMR (CDCl₃, 500 MHz) δ 8.37 (d, 1H), 7.90(d, 1H), 7.64 (t, 1H), 7.41 (m, 2H), 7.35 (d, 1H), 7.24 (t, 1H), 7.13(t, 1H), 7.07 (d, 1H), 5.17 (s, 1H), 4.00-3.71 (m, 8H), 3.28 (s, 2H),3.08 (m, 2H), 2.85 (m, 1H), 2.46 (m, 2H), 1.91 (m, 4H), 1.70 (m, 2H),1.53 (s, 6H), 1.11 (t, 3H) ppm.

Example 53 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(2-(1-isopropylpiperidin-4-yl)phenyl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA71

A mixture of compound A68 (70 mg, 0.12 mmol), acetone (2 mL),isopropanol (2 mL), and glacial acetic acid (38 mg, 0.62 mmol) in asealed vial was stirred at 120° C. for 2 hrs. After the mixture wascooled to room temperature, sodium borohydride (24 mg, 0.62 mmol) wasadded and the sealed vial was stirred at 80° C. for another 3 hrs. Thereaction mixture was basified with saturated aqueous sodium bicarbonateto pH 8. The volatiles were removed under reduced pressure and theresidue was purified by prep-HPLC to give compound A70 (40 mg, 53%yield) as a white solid: 97% purity (HPLC); MS m/z: 605.3 (M+1); ¹H NMR(CDCl₃, 500 MHz) δ 8.38 (d, 1H), 7.91 (d, 1H), 7.64 (t, 1H), 7.49-7.35(m, 3H), 7.24 (t, 1H), 7.13 (t, 1H), 7.07 (d, 1H), 5.15 (s, 1H),4.01-3.73 (m, 8H), 3.28 (s, 2H), 2.97 (m, 2H), 2.80 (m, 2H), 2.05 (m,2H), 1.78 (m, 2H), 1.70 (m, 2H), 1.53 (s, 6H), 1.04 (s, 6H) ppm.

Example 54 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(1-acetylpiperidin-4-yl)phenyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA72

A mixture of compound A68 (50 mg, 0.089 mmol), acetyl bromide (22 mg,0.18 mmol), and triethylamine (27 mg, 0.27 mmol) in dichloromethane (2mL) was stirred at room temperature for 2 hrs. The volatiles wereremoved under vacuum and the residue was purified by prep-HPLC to givecompound A72 (26 mg, 48% yield) as a white solid: 99% purity (HPLC); MSm/z: 605.3 (M+1); ¹H NMR (CDCl₃, 500 MHz) δ 8.36 (d, 1H), 7.91 (d, 1H),7.64 (t, 1H), 7.42 (m, 2H), 7.28-7.20 (m, 2H), 7.15 (t, 1H), 7.08 (d,1H), 5.15 (s, 1H), 4.78 (m, 1H), 4.00-3.74 (m, 9H), 3.42 (d, 1H), 3.20(d, J H), 3.05 (m, 1H), 2.97 (m, 1H), 2.48 (m, 1H), 2.10 (s, 3H),1.79-1.58 (m, 4H), 1.57 (s, 3H), 1.50 (s, 3H) ppm.

Example 55 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(1-(methylsulfonyl)piperidin-4-yl)phenyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA73

A mixture of compound A68 (50 mg, 0.089 mmol), methanesulfonyl chloride(51 mg, 0.44 mmol), and triethylamine (90 mg, 0.89 mmol) indichloromethane (4 mL) was stirred at room temperature for 1 hr. Thevolatiles were removed under vacuum and the residue was purified byprep-HPLC to give compound A73 (22 mg, 38% yield) as a white solid: 99%purity (HPLC); MS m/z: 641.3 (M+1); ¹H NMR (CDCl₃, 500 MHz) δ 8.37 (d,1H), 7.91 (d, 1H), 7.63 (t, 1H), 7.42 (m, 2H), 7.27 (m, 2H), 7.17 (m,1H), 7.08 (d, 1H), 5.18 (s, 1H), 3.97-3.71 (m, 10H), 3.29 (s, 2H), 2.92(m, 1H), 2.76 (s, 3H), 2.59 (m, 2H), 1.90-1.74 (m, 4H), 1.52 (s, 6H)ppm.

Example 56 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(pyrrolidin-3-yl)phenyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA74

Compound A74 was synthesized according to the procedure for compoundA68, substituting N-Boc-2,5-dihydropyrrole-4-boronic acid pinacol esterin place of N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacolester. The crude product was purified by prep-HPLC to give compound A74(13 mg) as a white solid: 92% purity (HPLC); MS m/z: 549 (M+1); ¹H NMR(CDCl₃, 500 MHz) δ 8.39 (d, 1H), 7.90 (d, 1H), 7.67 (t, 1H), 7.42 (m,2H), 7.35 (d, 1H), 7.27 (t, 1H), 7.14 (t, 1H), 7.05 (d, 1H), 5.23 (s,1H), 3.97-3.74 (m, 8H), 3.68 (m, 1H), 3.47-3.25 (m, 4H), 3.17 (m, 1H),2.93 (m, 1H), 2.25 (m, 1H), 1.92 (m, 1H), 1.51 (s, 6H) ppm.

Example 57 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(2-methyl-1-(2-(1-methylpyrrolidin-3-yl)phenyl)propan-2-yl)-6-morpholino-1,3,5-triazin-2-amineA75

Compound A75 was synthesized according to the procedure for compoundA69, substituting A74 in place of compound A68. The crude product waspurified by prep-HPLC to give compound A75 (21 mg) as a white solid: 98%purity (HPLC); MS m/z: 563.4 (M+1); ¹H NMR (CDCl₃, 500 MHz) h 8.40 (d,J=7.5 Hz, 1H), 7.91 (d, J=7.5 Hz, 1H), 7.65 (t, J_(HF)=53.5 Hz, 1H),7.50-7.38 (m, 3H), 7.26 (t, J=7.0 Hz, 1H), 7.11 (t, J=7.5 Hz, 1H), 7.01(d, J=7.5 Hz, 1H), 5.19 (s, 1H), 3.97-3.70 (m, 9H), 3.32 (s, 2H), 2.98(m, 1H), 2.85 (m, 1H), 2.72 (m, 1H), 2.48 (m, J H), 2.43 (s, 3H), 2.34(m, 1H), 1.88 (m, JH), 1.51 (s, 3H), 1.48 (s, 3H) ppm.

Example 58 Synthesis of4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(2-(3-(dimethylamino)propyl)phenyl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amine

A solution of compound A17 (0.30 g, 0.54 mmol),1-dimethylamino-2-propyne (0.13 g, 1.6 mmol),bis(triphenylphosphine)palladium(II) chloride (76 mg, 0.11 mmol), andcuprous iodide (21 mg, 0.11 mmol) in N,N′-dicyclohexylmethylamine (12mL) was stirred at 150° C. for 24 hrs. After cooling to roomtemperature, the mixture was diluted with water and extracted with ethylacetate. The combined organic fractions were washed with water, driedover sodium sulfate, and concentrated under vacuum to give crude4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(2-(3-(dimethylamino)prop-1-yn-1-yl)phenyl)-2-methylpropan-2-yl)-6-morpholino-1,3,5-triazin-2-amine(200 mg) as yellow oil, which was used directly in the next step withoutfurther purification: MS m/z: 561 (M+1).

A mixture of the crude alkyne (120 mg, 0.21 mmol) and 10% Pd/C (40 mg)in methanol (30 mL) was stirred under hydrogen at room temperatureovernight. The reaction mixture was filtered through Celite and thefiltrate was concentrated under vacuum. The residue was purified byprep-HPLC to give compound A76 (20 mg, 17% yield) as a white solid: 98%purity (HPLC); MS m/z: 565.3 (M+1); ¹H NMR (CDCl₃, 500 MHz) δ 8.41 (d,1H), 7.90 (d, 1H), 7.69 (t, 1H), 7.42 (m, 2H), 7.20 (m, 2H), 7.13 (m,1H), 7.05 (d, 1H), 5.31 (s, 1H), 3.95-3.75 (m, 8H), 3.26 (s, 2H),2.80-2.24 (m, 10H), 1.88 (m, 2H), 1.51 (s, 6H) ppm.

Example I A Luciferase-Based Luminescence Assay

PI3K catalyzes the conversion of phosphatidylinositol-4,5-bisphosphate(PIP2) and ATP to phosphatidylinositol-3,4,5-trisphosphate (PIP3) andADP. For all assays, the reaction buffer comprised 50 mM HEPES, pH 7.5,3 mM MgCl₂, 1 mM EGTA, 100 mM NaCl, 0.03% CHAPS and 2 mM DTT. Compoundsfor testing were dissolved and serially diluted in 100% DMSO (total of10 concentrations), then diluted 1:25 in reaction buffer.

PI3K alpha and PI3K delta enzymatic activity was determined by measuringthe amount of ATP consumed following the kinase reaction using aluciferase-based luminescence assay (KinaseGlo®, Promega Corp., Madison,Wis., USA). PI3K enzyme solutions were prepared by diluting PI3K alpha(Invitrogen Corp., Carlsbad, Calif., USA) or PI3K delta (Millipore,Billerica, Mass., USA) in reaction buffer, to 4× the final assayconcentration (final concentrations of enzymes were 1.65 nM and 6.86 nMfor PI3K alpha and PI3K delta, respectively). A substrate solution wasprepared by mixing PIP₂ and ATP in reaction buffer at 2× the final assayconcentration (final concentrations were 50 μM and 25 μM for PIP₂ andATP respectively). 2.5 μL each of the compound and kinase mixtures wereadded to individual wells of white low volume 384-well assay plates andmixed by shaking. The reactions were started by adding 5 μL of substratemixture per well and shaking. The assay plates were covered andreactions were allowed to proceed for 1 hour (PI3K alpha) or 2 hours(PI3K delta), after which 10 μL of Kinase Glo® reagent was added. Theplates were briefly centrifuged and incubated for 10 minutes, afterwhich luminescence was measured using a FlexStation plate reader(Molecular Devices, Sunnyvale, Calif., USA). IC₅₀ values were determinedby curve fitting using Graphpad Prism software (Graphpad Software, LaJolla, Calif., USA).

PI3K beta and gamma enzymatic activity was determined by measuring theamount of ADP produced following the kinase reaction using aluciferase-based luminescence assay (ADP Glo®, Promega Corp., Madison,Wis., USA). PI3K enzyme solutions were prepared by diluting PI3K beta(Millipore, Billerica, Mass., USA) or PI3K gamma (Invitrogen Corp.,Carlsbad, Calif., USA) in reaction buffer, to 4× the final assayconcentration (final concentrations of enzymes were 4.8 nM and 7.6 nMfor PI3K beta and PI3K gamma respectively). A substrate solution wasprepared by mixing PIP₂ and ATP in reaction buffer at 2× the final assayconcentration (final concentrations were 50 μM and 25 μM for PIP₂ andATP respectively). 2.5 μL each of the compound and kinase mixtures wereadded to individual wells of white low volume 384-well assay plates andmixed by shaking. The reactions were started by adding 5 μL of substratemixture per well and shaking. The assay plates were covered andreactions were allowed to proceed for 1 hour. Then, 5 μL of reaction mixwas transferred to another white low volume 384-well plate, and 5 μL ofADP-Glo™ reagent was added. The plates were briefly centrifuged andincubated for 40 minutes, after which 10 μL of kinase detection bufferwas added. The plates then were centrifuged briefly, shaken slowly andequilibrated at room temperature for 30 minutes, after whichluminescence was measured using a FlexStation plate reader (MolecularDevices, Sunnyvale, Calif., USA). IC₅₀ values were determined by curvefitting using Graphpad Prism software (Graphpad Software, La Jolla,Calif., USA).

The biological results of inhibition of enzymatic activity of PI3Ks aresummarized in Table 1, wherein A represents a value no greater than 100nM, B represents a value greater than 100 nM but less than 200 nM, Crepresents a value no less than 200 nM but no greater than 500 nM, and Drepresents a value greater than 500 nM; and wherein A′ represents aratio of greater than 20, B′ represents a ratio of no greater than 20but no less than 10, C′ represents a ratio of no greater than 10 but noless than 5, and D′ represents a ratio of no greater than 5.

TABLE 1 Biological Activity IC₅₀ α/δ β/δ γ/δ α/β Compound p110α p110βp110γ p110δ mTOR ratio ratio ratio ratio Ref 1 B B D’ A1  D A C’ A2  D DD C D D’ A’ D’ D’ A3  D D D’ A5  D D B C D C’ C’ D’ D’ A6  D D B’ A7  DD C B D C’ A’ D’ D’ A8  D D C’ A9  D D D’ A11 C A D’ A12 D C D’ A13 D DA’ A14 D A C A D A’ D’ A’ A’ A15 D B D A D A’ C’ A’ D’ A16 D A C A D A’D’ C’ A’ A17 D A C A D A’ D’ B’ A’ A18 D A C A D A’ D’ B’ A’ A19 D C C AD B’ B’ B’ D’ A20 D B D B D A’ D’ C’ A’ A21 D B D A D A’ B’ A’ C’ A22 DB C A D A’ C’ A’ C’ A23 D C C A D B’ D’ C’ D’ A24 D D C B D D’ C’ D’ D’A25 D D D C D D’ A’ D’ D’ A26 C A B B D D’ D’ D’ C’ A27 D A A A D A’ D’D’ B’ A29 D D D C D C’ A’ D’ D’ A30 D C D B D A’ D’ D’ B’ A33 C A C A DA’ D’ A’ B’ A35 D C D A D A’ A’ A’ B’ A39 D A C A D A’ D’ B’ A’ A40 C AC A D A’ D’ A’ B’ A41 D D D A D A’ A’ A’ D’ A43 C A D A D A’ D’ A’ A’A44 C A B A D A’ D’ A’ A’ A45 B A C A D A’ D’ A’ A’ A46 C A D A D A’ D’A’ A’ A47 C B D A D A’ B’ A’ D’ A49 D A C A D A’ D’ C’ A’ A50 D A D A DA’ C’ A’ B’ A51 D D C A D A’ B’ C’ D’ A52 D D A A D C’ B’ D’ D’ A59 D CD A D A’ A’ A’ C’ A60 D A D A D A’ D’ A’ A’ A61 D A D A D A’ D’ A’ A’A62 D D D A D A’ A’ A’ D’ A63 C A C A D A’ A’ A’ D’ A64 D A D A D A’ D’A’ A’ A65 D A B A D A’ D’ D’ A’ A66 D D D A D A’ A’ A’ D’ A67 D C D A DA’ B’ A’ D’ A68 D D D A D A’ A’ A’ D’ A70 D D D A D A’ A’ A’ C’ A71 D DD A D A’ A’ A’ D’ A72 B A A A D A’ D’ C’ A’ A73 C A B A D A’ D’ B’ A’A74 D D D A D A’ A’ A’ D’ A45 D D D A D A’ A’ A’ D’ A76 D C D A D A’ A’A’ C’

In Table 1, the α/δ ratio is the ratio of the IC₅₀ value of a compoundagainst PK3Kα over the IC₅₀ value of the same compound against PK3Kδ,and Ref. 1 isN-benzyl-4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-amine.

Example II ELISA Assay for PI3Kβ

Cellular PI3Kβ activity was determined by measuring the phosphorylationof AKT (Ser473) using an in-cell ELISA assay. PC-3 (prostate carcinoma)cells were obtained from ATCC (ATCC #CRL-1435). Growth medium was DMEM(CellGro #CV-10-013-CV) supplemented with 10% fetal bovine serum, 100IU/mL penicillin, 100 μg/mL streptomycin, and 1×MEM non-essential aminoacids. Phosphate buffered saline (PBS) contained 2.7 M NaCl, 54 mM KCl,86 mM Na₃PO₄ (dibasic, anhydrous), 28 mM K₃PO₄ (monobasic, anhydrous),pH 7.2, 10× stimulation mixture contained 50 μM LPA (Cayman #62215)diluted in serum-free DMEM medium (CellGro #CV-10-013-CV). Compounds fortesting were dissolved and serially diluted in 100% DMSO (total of 10concentrations), then diluted in serum-free DMEM to 2× final assayconcentration. 2× fixative solution contained 8% formaldehyde (Amresco#M134) diluted in PBS. Permeabilization solution contained PBSsupplemented with 0.1% Triton X-100. Blocking buffer was obtained fromLiCor (LiCor #927-40000). Wash buffer contained PBS supplemented with0.1% Tween-20. Primary antibody solution was rabbit anti-pAKT^(S473)monoclonal antibody (Cell Signaling #4060) and mouse anti-total S6(Santa Cruz #74459) diluted 1:500 and 1:2000, respectively, in blockingbuffer. Secondary antibody solution was IRDye 800CW-conjugated goatanti-rabbit IgG (LiCor #926-32211) and IRDye 680LT-conjugated goatanti-mouse IgG (LiCor #926-68020) diluted 1:2000 and 1:1000,respectively, in blocking buffer.

PC-3 cells were subcultured in growth medium and seeded into flat, clearbottom, 96-well plates (Corning #3904) at 16000 cells/well, thenincubated overnight in a 37° C., 5% CO₂ incubator. Growth medium inplates was replaced with 100 μL/well serum-free DMEM and incubatedovernight in a 37° C., 5% CO₂ incubator. 50 μL/well of fresh serum-freeDMEM was added to plates. Compound treatment was performed by adding 50μL/well of 2× compound mixture to plates and incubating for 2 hrs at 37°C., 5% CO₂, after which 11 μL/well of 10× stimulation mixture was addedand plates were incubated for 10 min at 37° C., 5% CO₂. Fixation wasperformed by adding 110 μL/well of 2× fixative solution to plates andincubating for 20 min at room temperature. Permeabilization wasperformed by replacing fixation solution with 150 μL/wellpermeabilization solution and incubating for 10 min at room temperature.Permeabilization was repeated (for a total of 2 times). Permeabilizationsolution was replaced with 100 μL/well blocking buffer and plates wereincubated for 1 hr at room temperature, after which 100 μL/well ofprimary antibody solution was added and plates were incubated overnightat 4° C. Plates were washed with wash buffer, after which 100 μL/well ofsecondary antibody solution was added to the plates and incubated in thedark for 1 hr at room temperature. Plates were washed with wash buffer,followed by awash with PBS. After completely removing PBS, plates werescanned on the Licor Odyssey Imager. Images quantified using LicorOdyssey application software. IC₅₀ values were determined by curvefitting using a Collaborative Drug Discovery database(www.collaborativedrug.com).

Example III ELISA Assay for PI3Kδ

Cellular PI3Kδ activity was determined by measuring the phosphorylationof AKT (Thr308) using a sandwich enzyme-linked immunosorbant assay(ELISA). Raji (Burkitt's Lymphoma) cells were obtained from ATCC (ATCC#CCL-86). Phosphate buffer saline (PBS) contained 2.7 M NaCl, 54 mM KCl,86 mM Na₃PO₄ (dibasic, anhydrous), and 28 mM K₃PO₄ (monobasic,anhydrous) at pH 7.2. Wash buffer contained PBS supplemented with 0.05%Tween-20. Blocking buffer contained wash buffer supplemented with 1%BSA. A 10× stimulation mixture contained 5 μg/mL anti-Human IgM antibody(Sigma #12386) diluted in serum-free RPMI medium (CellGro#CV-10-040-CV). Compounds for testing were dissolved and seriallydiluted in 100% DMSO (total of 10 concentrations), and then diluted inserum-free RPMI to 5×final assay concentration.

Raji cells were subcultured in RPMI medium supplemented with 10% fetalbovine serum, 100 IU/mL penicillin, 100 μg/mL streptomycin, and 1×MEMnon-essential amino acids. Sandwich ELISA plates were prepared bycoating 96-well assay plates (Pierce #15042) with 100 μL/well captureantibody (Cell Signaling Technology #7142 or 7144) diluted in PBS.Plates were incubated overnight at 4° C., then washed with wash buffer,after which 200 μL/well blocking buffer was added to the plates andincubated at room temperature for at least 2 hrs. Raji cells wereresuspended in serum-free RPMI medium and seeded into V-bottom, 2-mL96-well blocks (Corning #3961) at 10⁶ cells/well, then incubated for 2hrs in a 37° C., 5% CO₂ incubator. Compound treatment was performed byadding the 5× compound mixture to the cells and incubating for 2 hrs at37° C., 5% CO₂, after which the 10× stimulation mixture was added to theplates and incubated for 30 min at 37° C., 5% CO₂. Cells were pelletedby centrifuging plates at 1500 RPM for 5 min at room temperature. Mediawas carefully removed and cells were lysed by adding 100 μL/well celllysis buffer (Cell Signaling Technology #9803) supplemented withprotease and phosphatase inhibitors (Thermo Fisher #78443). Plates wereincubated on ice for 30 min, then the lysates (80 μL for pAKT^(T308), 10μL for total AKT) were transferred to prepared assay plates andincubated at 4° C. overnight. After washing plates with wash buffer, 100μL/well detection antibody (Cell Signaling Technology #7142 or 7144)diluted in blocking buffer was added to the plates and incubated for 1hr at 37° C. Plates were washed and 100 μL/well of HRP-conjugatedsecondary antibody (Cell Signaling Technology #7142 or 7144) diluted inblocking buffer was added to plates and incubated for 1 hr at roomtemperature. Plates were washed with wash buffer and 100 μL/well ofluminescent substrate was added to plates. After 1 min on a plate shakerat medium speed, luminescence was read on a Wallac Victor2 plate reader.IC₅₀ values were determined by curve fitting using a Collaborative DrugDiscovery database (www.collaborativedrug.com).

Example IV ELISA Assay for PI3Kα

PI3K alpha (PI3Kα) activity was determined by measuring thephosphorylation of AKT (Thr308) using an in-cell ELISA assay. MDA-MB-453(breast carcinoma) cells were obtained from ATCC (ATCC #HTB-131). Growthmedium was DMEM (CellGro #CV-10-013-CV) supplemented with 10% fetalbovine serum, 100 IU/mL penicillin, 100 μg/mL streptomycin, and 1×MEMnon-essential amino acids. Phosphate buffered saline (PBS) contained 2.7M NaCl, 54 mM KCl, 86 mM Na₃PO₄ (dibasic, anhydrous), and 28 mM K₃PO₄(monobasic, anhydrous) at pH 7.2. Stimulation mixture (10×) was 1000ng/mL LONG® R³ human IGF-1 (Sigma #I1271) diluted in serum-free DMEMmedium (CelIGro #CV-10-013-CV). Compounds for testing were dissolved andserially diluted in 100% DMSO (total of 10 concentrations), then dilutedin serum-free DMEM to 2× final assay concentration. Fixative solution(2×) was 8% formaldehyde (Amresco #M134) diluted in PBS.Permeabilization solution was PBS supplemented with 0.1% Triton X-100.Blocking buffer was obtained from LiCor (LiCor #927-40000). Wash bufferwas PBS supplemented with 0.1% Tween-20. Primary antibody solution wasrabbit anti-pAKT^(T308) monoclonal antibody (Cell Signaling #2965) andmouse anti-total S6 (Santa Cruz #74459) diluted 1:500 and 1:2000,respectively, in the blocking buffer. Secondary antibody solution wasIRDye 800CW-conjugated goat anti-rabbit IgG (LiCor #926-32211) and IRDye680LT-conjugated goat anti-mouse IgG (LiCor #926-68020) diluted 1:1000and 1:2000, respectively, in the blocking buffer.

MDA-MB-453 cells were subcultured in growth medium and seeded into flat,clear bottom, 96-well plates (Corning #3904) at 40000 cells/well, thenincubated overnight in a 5% CO₂ incubator at 37° C. Growth medium inplates was replaced with 100 μL/well serum-free DMEM and incubatedovernight at 37° C. in a 5% CO₂ incubator. Fresh serum-free DMEM (50μL/well) was added to plates. Compound treatment was performed by adding50 μL/well of 2× compound mixture to plates and incubating for 1 hr at37° C. and 5% CO₂, after which 11 μL/well of 10× stimulation mixture wasadded and plates were incubated for 10 min at 37° C. and 5% CO₂.Fixation was performed by adding 110 μL/well of 2× fixative solution tothe plates and incubating for 20 min at room temperature.Permeabilization was performed by replacing fixation solution with 150μL/well permeabilization solution and incubating for 10 min at roomtemperature. Permeabilization was repeated (for a total of 2 times).Permeabilization solution was replaced with 100 μL/well blocking bufferand plates were incubated for 1 hour at room temperature, after which100 μL/well of primary antibody solution was added and plates wereincubated overnight at 4° C. Plates were washed with wash buffer, afterwhich 100 μL/well of secondary antibody solution was added to the platesand incubated in the dark for 1 hr at room temperature. Plates werewashed with wash buffer, followed by a wash with PBS. After completelyremoving PBS, plates were scanned on the Licor Odyssey Imager. Imageswere quantified using Licor Odyssey application software. IC₅₀ valueswere determined by curve fitting using a Collaborative Drug Discoverydatabase (www.collaborativedrug.com).

Example V ELISA Assay for PI3Kγ

PI3K gamma (PI3Kγ) activity was determined by measuring thephosphorylation of AKT (Ser473) using an in-cell ELISA assay. RAW 264.7(mouse macrophage) cells were obtained from ATCC (ATCC #TIB-71). Growthmedium was DMEM (CellGro #CV-10-013-CV) supplemented with 10% fetalbovine serum, 100 IU/mL penicillin, 100 μg/mL streptomycin, and 1×MEMnon-essential amino acids. Phosphate buffered saline (PBS) contained 2.7M NaCl, 54 mM KCl, 86 mM Na₃PO₄ (dibasic, anhydrous), and 28 mM K₃PO₄(monobasic, anhydrous) at pH 7.2. Stimulation mixture (10×) was 500ng/mL recombinant human complement component C5a (R&D systems#2037-C5-025) diluted in serum-free DMEM medium (CellGro #CV-10-013-CV).Compounds for testing were dissolved and serially diluted in 100% DMSO(total of 10 concentrations), then diluted in serum-free DMEM to 2×final assay concentration. Fixative solution (2×) was 8% formaldehyde(Amresco #M134) diluted in PBS. Permeabilization solution was PBSsupplemented with 0.10% Triton X-100. Blocking buffer was obtained fromLiCor (LiCor #927-40000). Wash buffer was PBS supplemented with 0.1%Tween-20. Primary antibody solution was rabbit anti-pAKT^(S473)monoclonal antibody (Cell Signaling #4060) and mouse anti-total S6(Santa Cruz #74459) diluted 1:500 and 1:2000, respectively, in theblocking buffer. Secondary antibody solution was IRDye 800CW-conjugatedgoat anti-rabbit IgG (LiCor #926-32211) and IRDye 680LT-conjugated goatanti-mouse IgG (LiCor #926-68020) diluted 1:1000 and 1:2000,respectively, in the blocking buffer.

RAW 264.7 cells were subcultured in growth medium and seeded into flat,clear bottom, 96-well plates (Corning #3904) at 70000 cells/well, thenincubated overnight in a 37° C., 5% CO₂ incubator. Growth medium inplates was replaced with 100 μL/well serum-free DMEM and incubatedovernight in a 37° C., 5% CO₂ incubator. Fresh serum-free DMEM (50μL/well) was added to plates. Compound treatment was performed by adding50 μL/well of 2× compound mixture to plates and incubating for 2 hrs at37° C., 5% CO₂, after which 11 μL/well of 10× stimulation mixture wasadded and plates were incubated for 3 min at 37° C., 5% CO₂. Fixationwas performed by adding 110 μL/well of 2× fixative solution to platesand incubating for 20 min at room temperature. Permeabilization wasperformed by replacing fixation solution with 150 μL/wellpermeabilization solution and incubating for 10 min at room temperature.Permeabilization was repeated (for a total of 2 times). Permeabilizationsolution was replaced with 100 μL/well blocking buffer and plates wereincubated for 1 hr at room temperature, after which 100 μL/well ofprimary antibody solution was added and plates were incubated overnightat 4° C. Plates were washed with wash buffer, after which 100 μL/well ofsecondary antibody solution was added to the plates and incubated in thedark for 1 hr at room temperature. Plates were washed with wash buffer,followed by awash with PBS. After completely removing PBS, plates werescanned on the Licor Odyssey Imager. Images were quantified using LicorOdyssey application software. IC₅₀ values were determined by curvefitting using a Collaborative Drug Discovery database(www.collaborativedrug.com).

The biological results of inhibition of cellular enzymatic activity ofPI3Ks are summarized in Table 2, wherein A, B, C, D, A′, B′, C′, and D′are each as defined in Table 1.

TABLE 2 IC₅₀ α/δ β/δ γ/δ α/β Compound p110α p110β p110γ p110δ ratioratio ratio ratio A14 D A C A A’ A’ A’ B’ A15 D A C A A’ C’ A’ C’ A16 DA D A A’ A’ A’ B’ A17 C A A’ A18 D A C A A’ A’ A’ C’ A19 A A D’ A21 D BC A A’ A’ A’ A’ A22 D A C A A’ A’ A’ C’ A23 A A24 A A25 A A27 A A C’ A33A A A’ A’ A35 D A C A A’ A’ A’ A’ A39 D A B A A’ A’ A’ A40 D A C A A’ A’A’ A’ A41 D B D A A’ A’ A’ B’ A43 D A C A A’ A’ A’ C’ A44 D A A A A’ A’A’ A’ A45 C A A A A’ B’ A’ A’ A46 D A C A A’ B’ A’ A’ A49 D A C A A’ B’A’ B’ A50 D A C A A’ A’ A’ B’ A51 D B B A A’ D’ A’ C’ A52 D A B A A’ D’A’ C’ A59 D B D A A’ A’ A’ A’ A60 D C D A A’ A’ A’ A’ A61 D B D A A’ A’A’ A’ A62 D A C A A’ A’ A’ A’ A63 D A D A A’ A’ A’ A’ A64 D A D A A’ A’A’ A’ A65 D A C A A’ B’ A’ A’ A66 D B D A A’ A’ A’ A’ A67 D C D A A’ A’A’ A’ A68 D A C A A’ A’ A’ A’ A70 D A D A A’ A’ A’ A’ A71 D A D A A’ A’A’ A’ A72 C A A A A’ A’ A’ A’ A73 C A A A A’ C’ A’ A’ A74 D A C A A’ C’A’ A’ A75 D A B A A’ B’ A’ A’ A76 D A D A A’ A’ A’ A’

The examples set forth above are provided to give those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the claimed embodiments, and are not intended to limit thescope of what is disclosed herein. Modifications that are obvious topersons of skill in the art are intended to be within the scope of thefollowing claims. All publications, patents, and patent applicationscited in this specification are incorporated herein by reference as ifeach such publication, patent or patent application were specificallyand individually indicated to be incorporated herein by reference.

What is claimed is:
 1. A compound of Formula I:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: X, Y, and Z are each independently N or CR^(X), with the proviso that at least two of X, Y, and Z are nitrogen atoms; where R^(X) is hydrogen or C₁₋₆ alkyl; R¹ and R² are each independently (a)hydrogen, cyano, halo, or nitro, (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); wherein each R^(1a), R^(1b), R^(1c), and R^(1d) is independently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(1b) and R^(1c) together with the N atom to which they are attached form heterocyclyl; R³ and R⁴ are each independently hydrogen or C₁₋₆ alkyl; or R³ and R⁴ are linked together to form a bond, C₁₋₆ alkylene, C₁₋₆ heteroalkylene, C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene; R^(5a) is (a) hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₄ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); R^(5c) is —(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl) or —(CR^(5f)R^(5g))_(Q)-heteroaryl; R^(5d) and R^(5e) are each independently (a) hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); R^(5f) and R^(5g) are each independently (a)hydrogen or halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c); or —S(O)₂NR^(1b)R^(1c); or (d) when one occurrence of R^(5f) and one occurrence of R^(5g) are attached to the same carbon atom, the R^(5f) and R^(5g) together with the carbon atom to which they are attached form a C₃₋₁₀ cycloalkyl or heterocyclyl; R⁶ is hydrogen, C₁₋₆ alkyl, —S—C₁₋₆ alkyl, —S(O)—C₁₋₄, alkyl, or —SO₂—C₁₋₆ alkyl; m is 0 or 1; and n is 0, 1, 2, 3, or 4; wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in R¹, R², R³, R⁴, R⁶, R^(X), R^(1a), R^(1b), R^(1c), R^(1d), R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f) and R^(5g) is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^(a); and (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b), R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^(a); or (iii) R^(b) and R^(c) together with the N atom to which they are attached form heterocyclyl, which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q^(a); wherein each Q^(a) is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h), —NR^(c)C(O)NR^(f)R^(g), —NR^(c)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e), —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f), R^(g), and R^(h) is independently (i)hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) together with the N atom to which they are attached form heterocyclyl.
 2. The compound of claim 1, wherein the compound is not 4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-N-(2-phenyl-2-(pyrrolidin-1-yl)ethyl)-1,3,5-triazin-2-amine or 6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-N-(1-(4-((R)-3-(methoxymethyl)morpholino)phenyl)ethyl)-2-morpholinopyrimidin-4-amine.
 3. The compound of claim 1, wherein R^(5b) is (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, or heteroaryl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —S(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c).
 4. The compound of claim 1, wherein R^(5a) and R^(5b) are each independently (a) halo; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c).
 5. The compound of claim 4, wherein R^(5a) and R^(5b) are each methyl, optionally substituted with one or more halo.
 6. The compound of claim 1, wherein n is
 1. 7. The compound of claim 1, wherein R^(5f) and R^(5g) are each hydrogen.
 8. The compound of claim 1, wherein n is
 0. 9. The compound of claim 1, wherein m is
 0. 10. The compound of claim 1, having the structure of Formula Ia:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
 11. The compound of claim 1, having the structure of Formula Ib:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
 12. The compound of claim 1, having the structure of Formula II:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
 13. The compound of claim 12, having the structure of Formula IIa:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
 14. The compound of claim 12, having the structure of Formula IIb:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
 15. The compound of claim 1, wherein R^(5c) is C₆₋₁₄ aryl, optionally substituted with one or more substituents Q.
 16. The compound of claim 15, wherein R^(5c) is phenyl, optionally substituted with one or more substituents Q.
 17. The compound of claim 15, wherein R^(5c) is naphthyl, optionally substituted with one or more substituents Q.
 18. The compound of claim 1, wherein R^(c) is —(CR^(5f)R^(5g))_(n)—(C₆₋₁₄ aryl), wherein the aryl is optionally substituted with one or more substituents Q.
 19. The compound of claim 18, wherein R^(5c) is —(CH₂)-phenyl, wherein the phenyl is optionally substituted with one or more substituents Q.
 20. The compound of claim 18, wherein R^(5c) is —(CH₂)-naphthyl, wherein the naphthyl is optionally substituted with one or more substituents Q.
 21. The compound of claim 1, wherein R^(5c) is heteroaryl, optionally substituted with one or more substituents Q.
 22. The compound of claim 21, wherein R^(5c) is monocyclic heteroaryl, optionally substituted with one or more substituents Q.
 23. The compound of claim 21, wherein R^(c) is 5- or 6-membered heteroaryl, optionally substituted with one or more substituents Q.
 24. The compound of claim 21, wherein R^(k) is bicyclic heteroaryl, optionally substituted with one or more substituents Q.
 25. The compound of claim 1, wherein R^(5c) is —(CR^(5f)R^(5g))_(n)-heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents Q.
 26. The compound of claim 25, wherein R^(5c) is —(CR^(5f)R^(5g))_(n)-(monocyclic heteroaryl), wherein the heteroaryl is optionally substituted with one or more substituents Q.
 27. The compound of claim 25, wherein R^(5c) is —(CR^(5f)R^(5g))_(n)-(5- or 6-membered heteroaryl), wherein the heteroaryl is optionally substituted with one or more substituents Q.
 28. The compound of claim 25, wherein R^(5c) is —(CR^(5f)R^(5g))_(n)-(bicyclic heteroaryl), wherein the heteroaryl is optionally substituted with one or more substituents Q.
 29. The compound of claim 1, having the structure of Formula VII:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) are each independently (a) hydrogen, cyano, halo, or nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); or two of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) that are adjacent to each other form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q.
 30. The compound of claim 29, having the structure of Formula VIIa:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
 31. The compound of claim 29, having the structure of Formula VIIb:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
 32. The compound of claim 1, having the structure of Formula XI:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein: R^(7a), R^(7b), R^(7c), R^(7d), and R^(7c) are each independently (a) hydrogen, cyano, halo, or nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); or two of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) that are adjacent to each other form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q.
 33. The compound of claim 32, having the structure of Formula XIa:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
 34. The compound of claim 32, having the structure of Formula XIb:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
 35. The compound of claim 32, wherein R^(7a) is hydrogen, halo, C₁₋₆ alkyl optionally substituted with one or more substituents Q, or —OR^(1a).
 36. The compound of claim 35, wherein R^(7a) is hydrogen.
 37. The compound of claim 35, wherein R^(7a) is (a) cyano, halo, or nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c), —NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a), —S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c).
 38. The compound of claim 35, wherein R^(7a) is (i) halo; (ii) C₁₋₆ alkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) —OR^(1a) or —NR^(1b)R^(1c).
 39. The compound of claim 32, wherein R^(7b) is hydrogen, halo, C₁₋₆ alkyl optionally substituted with one or more substituents Q, or —OR^(1a).
 40. The compound of claim 39, wherein R^(7b) is hydrogen.
 41. The compound of claim 32, wherein R^(7c) is hydrogen, halo, C₁₋₆ alkyl optionally substituted with one or more substituents Q, or —OR^(1a).
 42. The compound of claim 41, wherein R^(7c) is hydrogen, halo, or —OR^(1a).
 43. The compound of claim 41, wherein R^(7c) is chloro.
 44. The compound of claim 41, wherein R^(7c) is —O—C₁₋₆ alkyl, optionally substituted with one or more substituents Q.
 45. The compound of claim 32, wherein R^(7d) is hydrogen, halo, C₁₋₆ alkyl optionally substituted with one or more substituents Q, or —OR^(1a).
 46. The compound of claim 45, wherein R^(7d) is hydrogen.
 47. The compound of claim 32, wherein R^(7e) is hydrogen, halo, C₁₋₆ alkyl optionally substituted with one or more substituents Q, or —OR^(1a).
 48. The compound of claim 47, wherein R^(7e) is hydrogen.
 49. The compound of claim 32, wherein two of R^(7a), R^(7b), R^(7c), R^(7d), and R^(7e) that are adjacent to each other form C₃₋₁₀ cycloalkenyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q.
 50. The compound of claim 49, wherein R^(7a) and R^(7b) together with the carbon atoms to which they are attached from C₆₋₁₄ aryl, optionally substituted with one or more substituents Q.
 51. The compound of claim 49, wherein R^(7b) and R^(7c) together with the carbon atoms to which they are attached from C₆₋₁₄ aryl, optionally substituted with one or more substituents Q.
 52. The compound of claim 1, wherein R^(5a) is hydrogen.
 53. The compound of claim 1, wherein R^(5a) is C₁₋₆ alkyl, optionally substituted with one or more substituents Q.
 54. The compound of claim 1, wherein R^(5a) is hydrogen, methyl, or ethyl.
 55. The compound of claim 1, wherein R^(5b) is C₁₋₆ alkyl, optionally substituted with one or more substituents Q.
 56. The compound of claim 55, wherein R^(5b) is methyl, ethyl, or propyl.
 57. The compound of claim 1, wherein R^(5b) is —C(O)OR^(1a).
 58. The compound of claim 57, wherein R^(5b) is —C(O)O—C₁₋₆ alkyl.
 59. The compound of claim 57, wherein R^(5b) is —C(O)OCH₃.
 60. The compound of claim 32, having the structure of Formula XV:

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
 61. The compound of claim 60, having the structure of Formula XVa:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
 62. The compound of claim 60, having the structure of Formula XVb:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
 63. The compound of claim 60, wherein R^(5a) is C₁₋₆ alkyl, optionally substituted with one or more substituents Q.
 64. The compound of claim 63, wherein R^(5a) is methyl.
 65. The compound of claim 60, wherein R^(5b) is C₁₋₆ alkyl, optionally substituted with one or more substituents Q.
 66. The compound of claim 65, wherein R^(5b) is methyl.
 67. The compound of claim 60, wherein R^(5a) and R^(5b) are methyl.
 68. The compound of claim 60, wherein R^(7a) is hydrogen, halo, C₁₋₆ alkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, where the alkyl, aryl, heteroaryl, and heterocyclyl are each optionally substituted with one or more substituents Q.
 69. The compound of claim 68, wherein R^(7a) is C₆₋₁₄ aryl, optionally substituted with one or more substituents Q.
 70. The compound of claim 69, wherein R^(7a) is phenyl, optionally substituted with one or more substituents Q.
 71. The compound of claim 69, wherein R^(7a) is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-(3-dimethylaminopropyl)phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-florophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 4-fluoro-3-methoxy phenyl, 3-methoxyphenyl, 4-methoxyphenyl, or 3-morpholin-4-ylmethylphenyl.
 72. The compound of claim 68, wherein R^(7a) is heteroaryl, optionally substituted with one or more substituents Q.
 73. The compound of claim 72, wherein R^(7a) is monocyclic heteroaryl, optionally substituted with one or more substituents Q.
 74. The compound of claim 72, wherein R^(7a) is 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q.
 75. The compound of claim 74, wherein R^(7a) is imidazolyl, pyrozolyl, pyridinyl, or pyrimidinyl, each optionally substituted with one or more substituents Q.
 76. The compound of claim 74, wherein R^(7a) is imidazol-1-yl, pyrozol-4-yl, 1-methyl-pyrozol-4-yl, 2-methylpyrozol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-(4-methylpiperazin-1-yl)pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl.
 77. The compound of claim 68, wherein R^(7a) is heterocyclyl, optionally substituted with one or more substituents Q.
 78. The compound of claim 77, wherein R^(7a) is monocyclic heterocyclyl, optionally substituted with one or more substituents Q.
 79. The compound of claim 77, wherein R^(7a) is 5- or 6-membered heterocyclyl, each optionally substituted with one or more substituents Q.
 80. The compound of claim 79, wherein R^(7a) is pyrrolidinyl, piperidinyl, or piperazinyl, each optionally substituted with one or more substituents Q.
 81. The compound of claim 79, wherein R^(7a) is pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.
 82. The compound of claim 60, wherein R^(7b) is hydrogen, halo, or C₁₋₆ alkyl optionally substituted with one or more substituents Q.
 83. The compound of claim 82, wherein R^(7b) is hydrogen.
 84. The compound of claim 60, wherein R^(7c) is hydrogen, halo, or C₁₋₆ alkyl optionally substituted with one or more substituents Q.
 85. The compound of claim 84, wherein R^(7c) is hydrogen.
 86. The compound of claim 60, wherein R^(7d) is hydrogen, halo, or C₁₋₆ alkyl optionally substituted with one or more substituents Q.
 87. The compound of claim 86, wherein R^(7d) is hydrogen.
 88. The compound of claim 60, wherein R^(7e) is hydrogen, halo, or C₁₋₆ alkyl optionally substituted with one or more substituents Q.
 89. The compound of claim 88, wherein R^(7e) is hydrogen.
 90. The compound of claim 60, wherein R^(7a) is C₆₋₁₄ aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; and R^(7b), R^(7c), R^(7d), and R^(7e) are hydrogen.
 91. The compound of claim 1, wherein R¹ is hydrogen.
 92. The compound of claim 1, wherein R¹ is —OR^(1a).
 93. The compound of claim 92, wherein R¹ is —O—C₁₋₆ alkyl.
 94. The compound of claim 92, wherein R¹ is methoxy.
 95. The compound of claim 1, wherein R² is hydrogen.
 96. The compound of claim 1, wherein R² is —NR^(1b)R^(1c).
 97. The compound of claim 96, wherein R² is amino.
 98. The compound of claim 1, wherein R³ is hydrogen.
 99. The compound of claim 1, wherein R⁴ is hydrogen.
 100. The compound of claim 1, wherein R⁶ is C₁₋₆ alkyl, optionally substituted with one or more substituents Q.
 101. The compound of claim 100, wherein R⁶ is methyl, fluoromethyl, difluoromethyl, or trifluoromethyl.
 102. The compound of claim 100, wherein R⁶ is difluoromethyl.
 103. The compound of claim 1, wherein X is N.
 104. The compound of claim 1, wherein X is CR^(X).
 105. The compound of claim 104, wherein X is CH.
 106. The compound of claim 1, wherein Y is N.
 107. The compound of claim 1, wherein Y is CR^(X).
 108. The compound of claim 107, wherein Y is CH.
 109. The compound of claim 1, wherein Z is N.
 110. The compound of claim 1, wherein Z is CR^(X).
 111. The compound of claim 110, wherein Z is CH.
 112. The compound of claim 1, wherein X, Y, and Z are N.
 113. The compound of claim 1 selected from the group consisting of:

and enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, and isotopic variants thereof; and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof.
 114. A pharmaceutical composition comprising the compound of claim 1, or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and one or more pharmaceutically acceptable excipients.
 115. The pharmaceutical composition of claim 114, wherein the composition is formulated for single dose administration.
 116. The pharmaceutical composition of claim 114, wherein the composition is formulated as an oral, parenteral, or intravenous dosage form.
 117. The pharmaceutical composition of claim 116, wherein the composition is formulated as an oral dosage form.
 118. The pharmaceutical composition of claim 117, wherein the oral dosage form is a tablet or capsule.
 119. The pharmaceutical composition of claim 114, further comprising a second therapeutic agent.
 120. A method for the treatment, prevention, or amelioration of one or more symptoms of a PI3K-mediated disorder, disease, or condition in a subject, which comprises administering to the subject the compound of claim
 1. 121. The method of claim 120, wherein the PI3K-mediated disorder, disease, or condition is an inflammatory disease.
 122. The method of claim 120, wherein the compound or the composition is administered in combination with a second therapeutic agent.
 123. A method for modulating PI3K enzymatic activity, comprising contacting a PI3K enzyme with the compound of claim
 1. 124. The method of claim 120, wherein the PI3K is a wild type.
 125. The method of claim 120, wherein the PI3K is a PI3K variant.
 126. The method of claim 120, wherein the PI3K is a Class I PI3K.
 127. The method of claim 126, wherein the PI3K is p110γ. 